Moxifloxacin hydrochloride, dexamethasone sodium phosphate.
1 mL of solution contains 5 mg moxifloxacin (equivalent to 5.45 mg moxifloxacin hydrochloride) and 1 mg dexamethasone (equivalent to 1.1 mg dexamethasone sodium phosphate).
Excipients/Inactive Ingredients: Sodium chloride, boric acid, sorbitol, tyloxapol, disodium edetate, sodium hydroxide and/or hydrochloric acid (to adjust pH), purified water.
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.
VIGADEXA is indicated in the treatment of ocular infections caused by susceptible microorganisms and in the prevention of inflammation and bacterial infection that may occur after ocular surgery.
Dosage regimen: To prevent post-surgical ocular inflammation and infection: Instill 1 drop 4 times per day in the eye to be operated, starting 1 day before the surgery and for 15 days after the surgery.
In patients who have undergone cataract surgery, instill the solution immediately after the surgery.
In patients who have undergone refractive surgery by LASIK, instill the solution within 15 minutes after the surgery.
In ocular infections caused by susceptible organisms: Instill 1 drop 4 times per day for 7 days, or as directed.
No cases of overdosage have been reported.
Due to the characteristics of this preparation, no toxic effects are to be expected with an ocular overdose of this product, nor in the event of accidental ingestion of the contents of one bottle.
Hypersensitivity to the active substance, any of the excipients or other quinolones.
Herpes simplex keratitis.
Vaccinia, varicella, and other viral infections of cornea or conjunctiva.
Fungal diseases of ocular structures or untreated parasitic eye infections.
Mycobacterial ocular infections.
In patients receiving systemic quinolones, serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria and itching. If an allergic reaction to moxifloxacin occurs, discontinue use of product. Serious acute hypersensitivity reactions require immediate emergency treatment. Oxygen and airway management should be administered as clinically indicated.
Prolonged use of ophthalmic corticosteroids may result in ocular hypertension and/or glaucoma, with damage to the optic nerve, reduced visual acuity and visual field defects, and posterior subcapsular cataract formation. In patients receiving prolonged ophthalmic corticosteroid therapy, intraocular pressure should be checked routinely and frequently. This is especially important in pediatric patients, as the risk of corticosteroid-induced ocular hypertension may be greater in children and may occur earlier than in adults.
The risk of corticosteroid-induced raised intraocular pressure and/or cataract formation is increased in predisposed patients (e.g. diabetes).
Tendon inflammation and rupture may occur with systemic fluoroquinolone therapy. Therefore, treatment with Vigadexa should be discontinued at the first sign of tendon inflammation. (See Adverse Reactions.)
Cushing's syndrome and/or adrenal suppression associated with systemic absorption of ophthalmic dexamethasone may occur after intensive or long-term continuous therapy in predisposed patients, including children and patients treated with CYP3A4 inhibitors (including ritonavir and cobicistat) (see Interactions). In these cases, treatment should not be discontinued abruptly, but progressively tapered.
Corticosteroids may reduce resistance to and aid in the establishment of nonsusceptible bacterial, fungal, viral or parasitic infections and mask the clinical signs of infection.
Fungal infection should be suspected in patients with persistent corneal ulceration. Corticosteroids therapy should be discontinued if fungal infection occurs.
Topical ophthalmic corticosteroids may slow corneal wound healing. Topical NSAIDs are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical steroids may increase the potential for healing problems (see Interactions).
In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical corticosteroids.
Prolonged use of antibiotics may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, discontinue use and institute alternative therapy.
General target population: Adults.
Special populations: Renal impairment: No studies have been conducted in subjects with renal impairment.
Hepatic impairment: No studies have been conducted in subjects with hepatic impairment.
For ocular use only.
To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip. Keep the bottle tightly closed when not in use. If using other eye drop or eye ointment medicines, leave at least 5 minutes between each medicine. Eye ointments should be administered last.
Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions.
Females and males of reproductive potential: There is limited clinical data to evaluate the effect of moxifloxacin or dexamethasone on male or female fertility. Moxifloxacin did not impair fertility in rats. No standard fertility studies are available with dexamethasone. (See Pharmacology: Toxicology under Actions.)
Use in Children: (below 18 years) Pediatric experience in clinical trials is limited; specific posology recommendations cannot be made.
Use in Elderly: There are limited data available on the use of Vigadexa in patients older than 65 years of age, but there is no evidence suggesting that a dosage regimen adjustment is required in geriatric patients.
Use in Pregnancy: Risk Summary: There are limited amount of data from the use of Vigadexa in pregnant women. Prolonged or repeated systemic corticoid use during pregnancy has been associated with an increased risk of intra-uterine growth retardation. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be observed carefully for signs of hypoadrenalism.
Studies in rats, rabbits and monkeys with systemic moxifloxacin showed reproductive toxicity at exposure levels greater than 25-fold compared to the human AUC at the recommended therapeutic dose. Reproductive toxicity was also seen in animal studies with dexamethasone, both after systemic and ocular administration at therapeutic dose levels.
Vigadexa is not recommended during pregnancy.
Animal data: In rats, oral moxifloxacin was not teratogenic up to the dose of 500 mg/kg/d. Decreased fetal body weight and delayed skeletal development were observed at 500 mg/kg/d. No-observed-adverse-effect-level (NOAEL) for developmental toxicity was 100 mg/kg/d. This results in a safety margin of about 30-fold compared to the human AUC at the recommended therapeutic dose.
In rabbits, two studies were performed using intravenous administration of moxifloxacin. Increased fetal malformations, abortions, maternal death as well as reduced placental and fetal weights were observed at 20 mg/kg/d. The NOAEL for developmental toxicity was determined to be 6.5 mg/kg/d, leading to a safety margin of about 245-fold compared to the human AUC at the recommended therapeutic dose.
In cynomolgus monkeys, moxifloxacin was administered by intragastric instillation from gestation day 20 to 50. At the maternal toxic doses of 30 and 100 mg/kg/d, increased abortion, vomiting and diarrhea were observed. Fetal body weights were reduced at 100 mg/kg/d. NOAEL for fetal toxicity was 10 mg/kg/d, providing a safety margin of about 174-fold compared to the human AUC at the recommended therapeutic dose.
In a peri- and postnatal development study in rats with moxifloxacin, maternal toxicity was seen at doses of 20 mg/kg/d and above. Decreased litter size (prenatal loss and pup mortality) and fetotoxicity (reduced body weight) were observed at 500 mg/kg/d. The NOAEL for pre- and postnatal development until weaning (F1) was determined to be 100 mg/kg/d.
In embryo fetal development studies with dexamethasone in mice, rats and rabbits, a number of malformations were seen at maternal toxic doses following systemic administration. Dexamethasone has also been shown to be teratogenic in mice and rabbits following topical ophthalmic application. The overall NOAEL for developmental toxicity was derived from an (oral) rat study and was based on embryotoxicity (0.01 mg/kg/d). This results in a dose ratio of about 0.24 (based on body surface area) compared to the recommended human ocular dose of 6.6 μg/kg/d.
Use in Lactation: Risk summary: It is unknown whether moxifloxacin and dexamethasone are excreted in human breast milk. Animal studies have shown excretion of low moxifloxacin levels in breast milk after oral administration. Although it is not likely that the amount of moxifloxacin and dexamethasone would be detectable in human milk or be capable of producing clinical effects in the infant following maternal use of the product, a risk to the breastfed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Tabulated summary of adverse drug reactions from clinical trials:
The following adverse reactions have been reported during clinical trials with Vigadexa and are classified according to the subsequent convention: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), and very rare (<1/10,000). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 1.)
Click on icon to see table/diagram/image
Adverse drug reactions from spontaneous reports and literature cases (frequency not known): The following adverse drug reactions have been derived from post-marketing experience with Vigadexa via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness. (See Table 2.)
Click on icon to see table/diagram/image
Additional adverse reactions reported with the individual components of Moxifloxacin/Dexamethasone Eye Drops, Solution are listed in the product information for Moxifloxacin Eye Drops, Solution and Dexamethasone Eye Drops, Solution.
Concomitant use of topical steroids and topical NSAIDs may increase the potential for corneal healing problems.
CYP3A4 inhibitors, including ritonavir and cobicistat, may increase systemic exposure resulting in increased risk of adrenal suppression/Cushing's syndrome (see Precautions.) The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid effects.
Instructions for use and handling: Not applicable.
Special precautions for disposal: Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Not applicable.
Do not store above 30°C.
Shelf-Life: Unopened: up to 24 months (5 mL) OR up to 18 months (2.5 mL).
In-use: 4 weeks after first opening of the bottle.
S03CA01 - dexamethasone and antiinfectives ; Belongs to the class of combinations of corticosteroids and antiinfectives used in ophthalmologic and otologic preparations.