Belvadox

Moxifloxacin + Dexamethasone Phosphate Eye Drops

Formulation
Each mL contains:

• Moxifloxacin (as hydrochloride), USP – 5mg
• Dexamethasone phosphate (as sodium), USP – 1mg
• Benzalkonium chloride, USP – 0.1mg
  (as preservative)
• Sterile aqueous vehicle – q.s.

Description
Moxifloxacin (as hydrochloride) + Dexamethasone phosphate (as sodium) Opthalmic solution is a colourless to pale yellow liquid.

Pharmacodynamics
This ophthalmic solution contains the antibiotic moxifloxacin hydrochloride, which destroys the susceptible bacteria that cause ocular infection and the anti-inflammatory dexamethesone phosphate (corticosteriod). The mechanism of action of moxifloxacin (and other fluoroquinolone antimicrobials) involves the inihibtions of bacterial topoisomerase IV and deoxyribonucleic acid (DNA) gyrase enzymes required for the DNA replication, transcription, repair, and recombination. In gram-negative bacteria, fluoroquionolones preferentially target DNA gyrase rather than topoisomerase IV, whereas in gram-positive bacteria, the target specificity is reversed. Corticosteroids achieve their anti-flammatory effects through decreased release of arachidonic acid as well as suppression of vascular endothelial cell adhesion molecules, cyclooxygenase and cytokine expression. This action results in a reduced release of pro-inflammatory mediators and reduced adhesion of circulating leukocytes to vascular endothelium, preventing their passage into inflamed ocular tissue. Additionally, decreased expression of cyclooxygenase results in a decreased production of inflammatory prostalglandins, which are known to cause breakdown of the blood aqueous barrier and leakage of plasma proteins into the ocular tissue.

Pharmacokinetics
Plasma concentrations of moxifloxacin were measured in healthy adult male and female subjects who received bilateral topical ocular doses of ophthalmic solution of moxifloxacin 0.5% 3 times a day. The mean steady-state Cmax (2.7mg/mL) and estimted daily-exposure AUC (45ng.hr/mL.) values were 1600 and 1000 times lower than the mean Cmax and AUC reported after therapeutic oral doses of moxifloxacin 400mg. The plasma half-life of moxifloxacin was estimated to be 13 hours. Dexamethasone phosphate is rapidly converted to dexamethasone in humans. Following topical administration of a single drop of ophthalmic solution of dexamethasone 0.1% in patients undergoing cataract surgery, aqueous humor levels of dexamethasone at 90-120 minutes post-dose average was 3.1+3.9 mg/mL.

Indications
To prevent post-surgery ocular inflammation and infection, instill 1 drop 4 times a day in the eye to be operated, starting 1 day before surgery and during 15 days after the surgery. In patients submitted to cataract surgery, instill the solution immediately after the surgery. In patients submitted to refractive surgery by LASIK, intill the solution within 15 minutes after the surgery.

In the ocular infections caused by susceptible organisms, instill 1 drop 4 times a day during 7 days, or as directed by the doctor.

Follow the doctor’s instructions on the schedule, dose and duration of treatment. Do not discontinue treatment without consulting the doctor. Do not use outdated medicine. Observe the appearance of the medicine before using it.

To prevent contaminating the dropper tip and solution, care should be taken not to touch any surfaces with the dropper tip of the bottle.

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 the other surfaces with the dropper tip. Keep the bottle tightly closed when not in use. If the patient is using other eye drop or eye ointment medicines, leave at least 15 minutes between each medicine. Eye ointments should be administrated last.

Method of Administration
For ocular use only. Not for injection. This solution should not be injected sub-conjunctivally or introduced directly into the anterior chamber of the eye.

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 of the bottle After cap is removed, if tamper evident snap collar is loose, remove before using the product. If more than one topical ophthalmic medicinal product is being used, the medicinal product must be administrated at least 5 minutes apart. Eye ointments should be administrated last.

Contraindications
Herpes simplex keratitis: Vaccinia, varicella, and other viral infections of cornea or conjunctiva; Mycobacterial ocular infections; Fungal diseases of ocular structures or untreated parasitic eye infections.
Hypersensitivity to the active substance, any of the excipients or other quinolones.

Special Warnings And Precautions For Use
In patients receiving systematically administrated qionolones, serious and occationally fatal hypersensitivity (anaphylactic) reactions have been reported, some of the following the first dose. Some reactions accompanied by cardiovascular collapse, Loss of consciousness, angioedema (including laryngeal, pharyngeal or facial oedema), airway obstruction, dyspnea, urticaria, and itching. If an allergic reaction to the product occurs, discontinue use of the medicinal product. Serious acute hypersensitivity reactions to moxifloxacin or any other product ingredient may require immediate emergency treament. Oxigen and airway management should be administrated where clinically indicated. As with other anti-infectives, prolonged use may result in overgrowth of non-susceptible organisms, including fungi. If superinspection occurs, discontinue use and institute alternative therapy Tendon inflammation and rupture may occur with systematic fluoroquinolone therapy including moxifloxacin, particularly in older patients and those treated concurrently with corticosteroids. Plasma concentrations of moxifloxacin were such lower than after therapeutic oral doses of moxifloxacin , however caution should be exercised while using this product and its use should be discontinued at the first sign of tendon inflammation.

Should not be use for the prophylaxis or empiric treatment of gonococcal conjunctivitis, including gonococcal ophthalmia neonatorum, beacause of the prevalence of fluoroquinolone-resistant Neisseria gonorrhoeae. Patients with eye infections caused by Neisseria gonorrhoeae should received appropriate systematic treatment. Patients should be advised not to wear contact lenses during treatment if they have signs of a bacterial ocular infection. This medicinal product contains phosphates which may lead to corneal deposits or corneal opacity when topically administered. It should be used with caution in patients presenting with compromised cornea and in instances where the patient is receiving polypharmacy with other phosphate-containing eye medications. Topical corticosteroids should not be used for longer than one week except under ophthalmic supervision. Prolonged use of topical ophthalmic corticosteroids may result in ocular hypertension and/or glaucoma, with damage to the optic nerve, reduced visual acuity, visual field defects and posterior subcapsular cataract formation. In patients receiving prolonged ophthalmic corticosteroid therapy, intraocular pressure and the lens should be checked routinely and frequently, particularly in patients with a history or presence of glaucoma. The dose of anti-glaucoma medication may need to be adjusted in these patients. Prolonged use may also increase the hazzard of secondary ocular infections. Topical ophthalmic corticosteroids may slow corneal wound healing. 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). In these cases, treatment should be progressively discontinued. Contact lenses should not be worn during treatment with corticosteroid eye drops due to increased risk of infection. Systemic absorption may be reduced by compressing the lacrimal sac at the medial canthus for a minute during and following the instillation of the drops. (This blocks the passage of drops via the naso-lacrimal duct to the wide absorptive area of the nasal and pharyngeal mucosa.)

Pregnancy
There are no or limited amount of data from the use of this product in pregnant women. However, studies in animals have shown that topically applied steroids can be absorb systematically and can cause abnormalities of foetal development in pregnant animals. Although the relevance of these findings to human has not been established, the use of this product during pregnancy should be avoided.

Breastfeeding
It is unknown whether moxifloxacin/metabolites are excreted in human milk. Animal studies have shown excretion of low levels in breast milk after oral administration of moxifloxacin. However, at therapeutic doses of this product no effects on the suckling child are anticipated. The medicinal product can be used during breast-feeding.

Fertility
Studies have not been performed to evaluate the effect of ocular administration of this product on fertility.

Interactions
No specific interaction studies have been performed with this product. Given the low systemic concentration of concentration of moxifloxacin following topical ocular administration of the medicinal product, drug interactions are unlikely to occur. The risk of increased intraocular pressure associated with prolonged corticosteroid therapy may be more likely to occur with concomitant use of anticholinergics, especially atropine and related compounds, in patients predisposed to acute angle closure. The risk of corneal deposits or corneal opacity may be more likely to occur in patients presenting with compromised cornea and receiving polypharmacy with other phosphate-containing eye medications. The following drug interactions are possible, but are unlikely to be of clinical significance. Following the use of eye drops in the eye: The therapeutic efficacy of dexamethasone may be reduced by phenytoin, phenobarbitone, ephedrine and rifampicin.

Glucocorticoids may increase the need for salicylate as plasma salicylate clearance is increased.

CYP3A4 inhibitors (including ritanovir and cobicistat) may decrease dexamethasone clearance resulting in increased effects and adrenal suppression/Cushing’s syndrome. The combination should be avoided unless the benefit outweighs the increased risk if systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid effects.

If more than one topical ophthalmic medicinal product is being used, the medicines must be administered at least 5 minutes apart. Eye ointments should be administered last.

Adverse Drug Reactions
Tabulated list of adverse reactions: The following adverse reactions have been reported during clinical trials with Moxifloxacin/Dexamethasone (Modexeye) Sterile Ophthalmic Solution 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 below)

System organ Classification	MedDRA Term (v. 15.0)
Psychiatric disorders	Rare: insomnia
Nervous System Disorders	Uncommon: dysgeusia
Eye disorders	Common: Eye Pruritus, eye irritation Uncommon: Vision blurred, eyelid pain
Respiratory, thoracic and mediastinal disorders	Uncommon: oroparyngeal pain

Overdose
The limited holding capacity of the conjunctival sac for ophthalmic products practically precludes any overdosing of the medicinal product. The total amount of moxifloxacin in the container is too small to induce adverse effects after accidental ingestion.

ADR Reporting Statement
For suspected adverse drug reaction, report to the FDA: www.fda.gov.ph. Seek Medical attention immediately at the first sign of any adverse drug reaction.

Storage Condition
Store at temperatures not exceeding 30°C.
Keep out of reach of children.

Dosage Form And Packaging Available
Ophthalmic Solution, 5 mL opaque plastic bottle wiith nozzle and cap (Box of 1’s)

Caution
Food, Drugs, Devices and Cosmetics Act prohibits dispensing without prescription.

For suspected adverse drug reaction, report to the FDA: www.fda.gov.ph. Seek medical attention immediately at the first sign of any adverse drug reaction.

FDA Registration No.
DRP-13712-03