Combidar Eye Drops

Combidar

Tobramycin + Dexamethasone Eye Drops

Formulation
Each mL contains:

Tobramycin Sulfate, USP eq. to Tobramycin – 0.3%w/v
Dexamethasone Sodium Phosphate, USP eq. to Dexamethasone – 0.1%w/v
Benzalkonium Chloride Solution, BP – 0.02%v/v
(As Preservative)
Water for Injections, BP – q.s.

Pharmacodynamic Properties
Mechanism of action
Dexamethasone is a potent corticoid. Corticoids suppress the inflammatory response to a variety of agents and they can delay or slow healing. Since corticoids may inhibit the body’s defense mechanism against infection, a concomitant antimicrobial drug may be used when this inhibition is considered to be clinically significant. Tobramycin is an antibacterial drug. It inhibits the growth of bacteria by inhibiting protein synthesis. Tobramycin is included in this combination product to provide action against susceptible bacteria.

Pharmacokinetic Properties
In a multi-center, double-masked, parallelgroup, randomized, single-dose pharmacokinetic study in male and female cataract surgery patients, mean dexamethasone concentrations following administration of were similar to dexamethasone concentrations following administration of tobramycin /dexamethasone ophthalmic solution 0.3%/0.1%. Aqueous humor concentrations reached a mean peak of 33.7 ng/mL2 hours following single-dose administration of tobramycin /dexamethasone ophthalmic solution.

No data are available on the extent of systemic absorption of dexamethasone or tobramycin from tobramycin /dexamethasone ophthalmic solution. Following multiple-dose (QID for 2 days) bilateral ocular administration of tobramycin /dexamethasone ophthalmic solution.

(Tobramycin 0.3%/Dexamethasone 0.1% ophthalmic solution) in healthy male and female volunteers, peak plasma concentrations of dexamethasone were less than 1 mg/mL and occurred within 2 hours post-dose across all subjects.

Indications
Tobramycin and dexamethasone ophthalmic solution is a topical antibiotic and corticosteroid combination for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists.

Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe where the inherent risk of steroid use in certain infective conjunctivitides is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or from chemical, radiation or thermal burns, or penetration of foreign bodies

The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye.

The particular anti-infective drug in this product is active against the following common bacterial eye pathogens: Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin- resistant isolates. Streptococci, including some Group A and other beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae. Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris isolates, Haemophilus influenzae, H aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species.

Dosage And Mode/Route of Administration
Instill one drop into the conjunctival sac(s) every four to six hours. During the initial 24 to 48 hours, the dosage may be increased to one drop every two hours. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely.

Contraindications
Hypersensitivity to tobramycin or dexamethasone or to any of the excipients.
Herpes simplex keratitis.
Vaccinia, varicella and other viral disease of the cornea and conjunctiva.
Mycobacterial infections of the eye caused by, but not limited to, acid-fast bacilli such as Mycobacterium tuberculosis, Mycobacterium leprae, or Mycobacterium avium.
Fungal diseases of ocular structures or untreated parasitic eye infections. Untreated purulent infection of the eye.

Special Warnings And Precaution
Tobramycin and dexamethasone ophthalmic solution is for topical use only and not for injection or oral use.

Prolonged use of topical ophthalmic corticosteroids (i.e. longer than the maximum duration used in clinical trials [24 days] may result in ocular hypertension/glaucoma with resultant damage to the optic nerve and reduced visual acuity and visual fields defects and may also result in posterior subcapsular cataract formation.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

It is advisable that the intraocular pressure be checked frequently. This is especially important in pediatric patients receiving dexamethasone-containing products, as the risk of steroid-induced ocular hypertension may be greater in children below 6 years of age and may occur earlier than a steroid response in adults. The frequency and duration of treatment should be carefully considered, and the intraocular pressure should be monitored from the outset of treatment, recognizing the risk for earlier and greater steroid-induced intraocular pressure increases in the paediatric patients.

Cushing’s syndrome and/or adrenal suppression associated with systemic absorption of ocular dexamethasone may occur after intensive or long-term continuous therapy in predisposed patients, including children and patients treated with CYP3A4 inhibitors. In these cases, treatment should be progressively discontinued. The risk of corticosteroid-induced raised intraocular pressure and/or cataract formation is increased in predisposed patients (e.g. diabetes).

Prolonged use may also result in secondary ocular infections due to suppression of host response. Corticosteroids may reduce resistance to and aid in the establishment of bacterial, viral, fungal or parasitic infections and mask the clinical signs of infection.

Sensitivity to topically administered aminoglycosides may occur in some patients. Severity of hypersensitivity reactions may vary from local efects to generalized reactions such as erythema, itching, urticarial, skin rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If hypersensitivity develops during use of this medicine, treatment should be discontinued.

Cross-hypersensitivity to other aminoglycosides can occur, and the possibility that patients who become sensitized to topical tobramycin may also be sensitive to other topical and/or systemic aminoglycosides should be considered. Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic aminoglycoside therapy. Caution is advised when eye drops are used concomitantly with systemic aminoglycosides. Caution should be exercised when prescribing Eye Drops to patients with known or suspected neuromuscular disorders such as myasthenia gravis or Parkinson’s disease. Aminoglycosides may aggravate muscle weakness because of their potential effect on neuromuscular function Fungal infection should be suspected in patients with persistent corneal ulceration. If fungal infection occurs, corticosteroids therapy should be discontinued. Prolonged use of antibiotics such as tobramycin may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

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.

In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical corticosteroids.

Benzalkonium chloride, used as a preservative in this product, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Benzalkonium chloride may cause eye irritation and discolour soft contact lenses.

Avoid contact with soft contact lenses. Contact lens wear is not recommended during treatment of an ocular infection or inflammation. If patients are allowed to wear contact lenses, they must be instructed to remove lenses prior to application of eye drops and wait at least 15 minutes before reinsertion.

Interaction With Other Medicinal Products And Other Forms Of Interaction
No clinically relevant interactions have been described with topical ocular dosing.
Concomitant use of topical steroids and topical NSAIDs may increase the potential for corneal healing problems. Dexamethasone is metabolized via cytochrome P450 3A4 (CYP3A4). CYP3A4 inhibitors (including ritonavir 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 of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid effects

Pregnancy
There are no or limited amount of data from the topical ocular use of tobramycin and dexamethasone in pregnant women. Tobramycin does cross the placenta into the fetus after intravenous dosing in pregnant women. Tobramycin is not expected to cause ototoxicity from in utero exposure. Prolonged or repeated 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 animals have shown reproductive toxicity after systemic administration of tobramycin and dexamethasone. These effects were observed at exposures considered sufficiently in excess of the maximum human ocular dosage delivered from the maternal use of the product.

Tobramycin and dexamethasone ophthalmic solution is not recommended during pregnancy

Breastfeeding
Tobramycin is excreted in human milk after systemic administration. No data is available on the passage of dexamethasone into human breast milk. It is unknown whether tobramycin and dexamethasone are excreted in human milk following topical ocular administration. It is not likely that the amount of Tobramycin and Dexamethasone would be detectable in human milk or be capable of producing clinical effects in the infant following topical use of the product.

A risk to the suckling 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.

Fertility
Studies have not been performed to evaluate the effect of tobramycin on human or animal fertility. There is limited clinical data to evaluate the effect of dexamethasone on male or female fertility.

Adverse Drug Reactions
Adverse reactions have occurred with steroid/anti-infective combination drugs which can be attributed to the steroid component, the anti-infective component, or the combination. Exact incidence figures are not available. The most frequent adverse reactions to topical ocular tobramycin are hypersensitivity and localized ocular toxicity, including eye pain, eyelids pruritus, eyelid edema, and conjunctival hyperemia. These reactions occur in less than 4% of patients. Similar reactions may occur with the topical use of other aminoglycoside antibiotics.

The reactions due to the steroid component are: increased intraocular pressure (IOP) with possible development of glaucoma, and infrequent optic nerve disorder; subcapsular cataract; and impaired healing.

Secondary Infection.
The development of secondary infection has occurred after use of combinations containing steroids and antimicrobials. Fungal infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. The possibility of fungal invasion must be considered in any persistent corneal ulceration where steroid treatment has been used. Secondary bacterial ocular infection following suppression of host responses also occurs. Non-ocular adverse events occurring at an incidence of 0.5% to 1% included headache and increased blood pressure.

Overdosage And Treatment
In the case of overdose, drug concentrations would not be reduced by hemodialysis or peritoneal dialysis. there is no specific antidote. Treatment should be symptomatic.

Caution
Foods, Drugs, Devices and Cosmetics Act prohibits dispensing without permission.

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.

Dosage Form And Packaging Available (Pack Size)
Opaque plastic bottle x 5 mLwith nozzle and cap (Box of 1’s)

FDA Registration No.
DRP-14088-01