Tobramycin; dexamethasone (Tobradex) is an ophthalmic preparation that combines tobramycin (an aminoglycoside antibiotic) with dexamethasone (a corticosteroid). The combination is used to treat corticosteroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial infection exists. TobraDex ST (tobramycin 0.3%; dexamethasone 0.05%) utilizes a novel suspension technology as compared to TobraDex (tobramycin 0.3%; dexamethasone 0.1%). Tobradex (tobramycin 0.3%; dexamethasone 0.1%) was approved by the FDA in August 1988. Tobradex ST (tobramycin 0.3%; dexamethasone 0.05%) was approved by the FDA in February 2009.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Ophthalmic Administration
-Wash hands before and after use.
-Avoid contamination; do not touch the tip of the container to the eye, fingertips, or other surface.
-To avoid contamination or the spread of infection, do not use any individual product package for more than one person.
-Do not wear contact lenses while using this product.
Instillation:
-OINTMENT: Tilt head back and pull the lower eyelid down with the index finger to form a pouch. Place a small amount (about one-half of an inch) of the ointment into the pouch. Look downward before closing your eye.
-SUSPENSION: Shake well before using. Tilt head back slightly and pull the lower eyelid down with the index finger to form a pouch. Squeeze the prescribed number of drops into the pouch and gently close eyes for 1 to 2 minutes. Do not blink.
Hypertension has been reported in 0.5% to 1% patients using tobramycin; dexamethasone.
Prolonged use of ophthalmic dexamethasone, such as tobramycin; dexamethasone, may cause ocular hypertension with possible development of glaucoma and optic neuritis (infrequent); posterior subcapsular cataracts; and impaired wound healing. In patients with corneal or scleral thinning, administration of topical ophthalmic corticosteroids have caused perforations.
Use of tobramycin; dexamethasone ophthalmic may worsen the infectious condition. In acute purulent conditions and parasitic infections of the eye, corticosteroids may mask infection or enhance existing infection. Secondary infection or superinfection has occurred following use of combinations containing a corticosteroid and antimicrobial. Fungal infections of the cornea are particularly prone to develop coincidentally with long-term application of ophthalmic corticosteroids. The possibility of fungal invasion must be considered in any persistent corneal ulceration where corticosteroid treatment has been used. Secondary bacterial ocular infection following suppression of host immune responses also occurs. The ophthalmic ointment may retard corneal wound healing.
Hypersensitivity reactions for tobramycin; dexamethasone has ranged from local effects to generalized reactions such as erythematous reactions, pruritus, urticaria, skin rash, anaphylaxis, anaphylactoid reactions, or bullous rash. Erythema multiforme and anaphylactic reactions have been reported with the in postmarketing reports.
The most frequent adverse reactions to ophthalmic tobramycin are hypersensitivity and localized ocular toxicity, including ocular pain, conjunctival hyperemia, eyelid itching and swelling/edema (blepharitis), ocular pruritus, and conjunctival erythema. These reactions occur in less than 4% of patients using single ingredient tobramycin ophthalmic products. Similar reactions may occur with ophthalmic use of tobramycin combination products such as tobramycin; dexamethasone. Temporary blurred vision may occur after the dose of tobramycin; dexamethasone.
There have been reports of bacterial keratitis associated with the use of multiple dose containers of topical ophthalmic products like tobramycin; dexamethasone. These containers had been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface.
Headache has been reported in 0.5% to 1% of patients using tobramycin; dexamethasone.
The use of dexamethasone-containing products in excess of the recommended dose may result in Cushing's syndrome and adrenal suppression in patients who are predisposed, such as pediatric patients and patients receiving concurrent treatment with a CYP3A4 inhibitor.
Systemic use of aminoglycosides, such as tobramycin, has been associated with cases of neurotoxicity, ototoxicity, and nephrotoxicity.
Use of tobramycin; dexamethasone is contraindicated in patients with hypersensitivity to any component of the combination product. Tobramycin should not be used in patients with a history of aminoglycoside hypersensitivity. Cross-sensitivity with other aminoglycoside antibiotics may occur. Dexamethasone may mask signs and symptoms of tobramycin hypersensitivity. Use with caution in patients with previous corticosteroid hypersensitivity. If hypersensitivity develops, discontinue use and institute appropriate therapy.
Do not wear contact lenses while using tobramycin; dexamethasone. Additionally, suspensions are formulated with the preservative benzalkonium chloride, which may be absorbed by soft contact lenses.
Dexamethasone can cause local immunosuppression in the eye. Tobramycin; dexamethasone combination products should not be used in patients with preexisting ocular infection of the cornea and conjunctiva that are not susceptible to tobramycin; the products are contraindicated in patients with viral infection due to herpes simplex (epithelial herpes simplex keratitis or dendritic keratitis), vaccinia, or varicella, and in those with fungal infection or mycobacterial infection of the eye or eye structures.
Evaluate for increased intraocular pressure (IOP) and perform ophthalmic examination with the aid of magnification, such as slit lamp biomicroscopy, and where appropriate fluorescein staining prior the initiation of tobramycin; dexamethasone and the renewal of the medication order. If ocular signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. If tobramycin; dexamethasone is used for 10 days or longer, intraocular pressure should be monitored.
Corticosteroids have been found to be teratogenic in animal studies. There are no adequate and well-controlled studies in pregnant women. However, prolonged or repeated corticosteroid use during pregnancy has been associated with an increased risk of intra-uterine growth retardation. Tobramycin and dexamethasone ophthalmic products should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be observed carefully for signs of hypoadrenalism.
According to the FDA-approved labeling, caution should be exercised when tobramycin; dexamethasone is administered to breast-feeding mothers. It is not known if ophthalmic administration of dexamethasone could result in sufficient systemic absorption to produce detectable quantities in breast milk. However, pharmacokinetic studies indicate that systemic absorption after ophthalmic administration of dexamethasone is limited, and therefore it is unlikely that a significant amount of drug would be excreted into breast milk. When used in low doses, systemically administered corticosteroids (e.g., prednisone) are distributed into breast milk in quantities not likely to have a deleterious effect on the infant. Aminoglycosides are generally excreted into breast milk in low concentrations. However, they are poorly absorbed from the gastrointestinal tract and are not likely to cause adverse events in nursing infants. Tobramycin breast milk concentrations after systemic administration are around 0.52 mcg/mL. Several aminoglycosides are considered compatible with breast-feeding. While the use of dexamethasone in breast-feeding mothers has not been studied, previous American Academy of Pediatrics (AAP) recommendations considered other corticosteroids, such as prednisone and prednisolone, to be usually compatible with lactation. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Due to their effect on neuromuscular function, aminoglycosides (e.g., tobramycin) may aggravate muscle weakness in patients with neuromuscular disease such as myasthenia gravis or parkinsonism (Parkinson's disease).
Vision may be temporarily blurred after use of tobramycin; dexamethasone. Advise patients (or caregivers) to use caution when driving or operating machinery or when performing activities requiring coordination and concentration if vision is not clear (i.e., blurred vision).
Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Acinetobacter calcoaceticus, Escherichia coli, Haemophilus aegyptius, Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Klebsiella aerogenes, Klebsiella pneumoniae, Moraxella lacunata, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Staphylococcus aureus (MRSA), Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci)
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.
For the treatment of corticosteroid-responsive ocular inflammation where superficial bacterial ophthalmic infection or a risk of bacterial infection exists, such as allergic conjunctivitis, dry eye disease*, eyelid acne rosacea, superficial punctate keratitis, herpes zoster ocular infection associated keratitis, iritis, cyclitis, uveitis, and selected infective bacterial conjunctivitis and viral conjunctivitis, where the inherent hazard of steroid use is accepted to obtain an advisable diminution in edema and inflammation and for corneal abrasion, corneal ulcer, or corneal injury from chemical, radiation, or thermal ocular burns or penetration of foreign bodies:
-for the treatment of corticosteroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where a superficial bacterial ophthalmic infection or a risk of bacterial infection exists:
Ophthalmic dosage (tobramycin 0.3% and dexamethasone 0.1% ophthalmic suspension):
Adults: 1 to 2 drops in the affected eye(s) every 4 to 6 hours, initially. May increase the dose to 1 to 2 drops in the affected eye(s) every 2 hours if needed for the first 24 to 48 hours. Reduce dose gradually as warranted by clinical improvement.
Children and Adolescents 2 to 17 years: 1 to 2 drops in the affected eye(s) every 4 to 6 hours, initially. May increase the dose to 1 to 2 drops in the affected eye(s) every 2 hours if needed for the first 24 to 48 hours. Reduce dose gradually as warranted by clinical improvement.
Ophthalmic dosage (tobramycin 0.3% and dexamethasone 0.05% ophthalmic suspension):
Adults: 1 drop in the affected eye(s) every 4 to 6 hours, initially. May increase the dose to 1 drop in the affected eye(s) every 2 hours if needed for the first 24 to 48 hours. Reduce dose gradually as warranted by clinical improvement.
Children and Adolescents 2 to 17 years: 1 drop in the affected eye(s) every 4 to 6 hours, initially. May increase the dose to 1 drop in the affected eye(s) every 2 hours if needed for the first 24 to 48 hours. Reduce dose gradually as warranted by clinical improvement.
Ophthalmic dosage (tobramycin 0.3% and dexamethasone 0.1% ophthalmic ointment):
Adults: 0.5 inch ribbon in the affected eye(s) up to 3 to 4 times daily.
Children and Adolescents 2 to 17 years: 0.5 inch ribbon in the affected eye(s) up to 3 to 4 times daily.
-for the treatment of dry eye disease* with known or suspected ophthalmic infection:
Ophthalmic dosage (tobramycin 0.3% and dexamethasone 0.1% ophthalmic ointment):
Adults: 0.5 inch ribbon in each eye 4 times daily, initially. Reduce dose to 0.5 inch ribbon in each eye twice daily after 1 to 2 weeks if positive response in signs and/or symptoms and start cyclosporine, then taper or discontinue steroid therapy after 2 to 4 weeks. Consider extending duration to 4 weeks if no response at 2 weeks, especially in patients with moderate to severe disease.
Maximum Dosage Limits:
-Adults
20 mL ophthalmic suspension or 8 g ophthalmic ointment per treatment course.
-Geriatric
20 mL ophthalmic suspension or 8 g ophthalmic ointment per treatment course.
-Adolescents
20 mL ophthalmic suspension or 8 g ophthalmic ointment per treatment course.
-Children
2 to 12 years: 20 mL ophthalmic suspension or 8 g ophthalmic ointment per treatment course.
1 year: Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Neonates
Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
No dosage adjustments are needed for ophthalmic topical application.
Patients with Renal Impairment Dosing
No dosage adjustments are needed for ophthalmic topical application.
*non-FDA-approved indication
There are no drug interactions associated with Tobramycin; Dexamethasone products.
Mechanism of Action:-Tobramycin: Tobramycin is bactericidal in action. Similar to other aminoglycosides, it works by inhibiting bacterial protein synthesis through irreversible binding to the 30 S ribosomal subunit of susceptible bacteria. Tobramycin is actively transported into the bacterial cell where it binds to receptors present on the 30 S ribosomal subunit. This binding interferes with messenger RNA (mRNA). As a result, abnormal, nonfunctional proteins are formed due to misreading of the bacterial DNA. Eventually, susceptible bacteria die because of the lack of functional proteins. One aspect essential to aminoglycoside lethality is the need to achieve intracellular concentrations in excess of extracellular. Anaerobic bacteria are not susceptible to aminoglycosides due, at least in part, to a lack of an active transport mechanism for aminoglycoside uptake.
-Dexamethasone: Dexamethasone inhibits the inflammatory response to chemical, immunologic, or mechanical agents. Although the precise mechanism of action is unknown, the antiinflammatory actions are thought to involve phospholipase A2 inhibitory proteins, collectively called lipocortins. Lipocortins, in turn, control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the precursor molecule arachidonic acid. Dexamethasone inhibits edema, fibrin deposition, capillary dilatation, and migration of leukocytes and phagocytes in the acute inflammatory response. It may also reduce capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation. Dexamethasone also inhibits the body's immune response against infection, and it may reduce the outflow of aqueous humor, thereby increasing intraocular pressure and inducing or aggravating open-angle glaucoma.
Against gram-negative aerobic rods, aminoglycosides exhibit 'concentration-dependent killing' and a 'post-antibiotic effect' (PAE). 'Concentration-dependent killing' describes the principle that bactericidal effects increase as the concentration increases. PAE is where suppression of bacterial growth continues after the antibiotic concentration falls below the bacterial MIC. The post-antibiotic effect can be bacteria specific, as well as drug specific. The PAE of aminoglycosides is short for most gram-positive organisms (less than 2 hours) and longer for gram-negative organisms (2 to 8 hours), such as E. coli, K. pneumoniae, and P. aeruginosa. Both of these phenomena are being exploited in designing dosage regimens that employ higher doses administered at longer intervals. The major pharmacodynamic parameter that determines efficacy of aminoglycosides is the serum peak concentration to MIC ratio (peak/MIC). Both time-kill studies and studies in humans have shown that a peak/MIC of more than 8 to 12/1 is associated with successful regimens.
Tobramycin is active against gram-negative Enterobacteriaceae organisms including Escherichia coli, Proteus sp., Klebsiella sp., Serratia sp., Enterobacter sp., and Citrobacter sp. In general, Pseudomonas aeruginosa is usually sensitive to aminoglycosides and frequently is more sensitive to tobramycin than to gentamicin; its susceptibility, however, is considerably variable. Other pseudomonal species also may be susceptible but are usually less so than Pseudomonas aeruginosa. Synergistic bactericidal effects can be achieved when vancomycin or beta-lactams are combined with gentamicin against gram-positive organisms, such as Staphylococcus aureus and Enterococcus sp.
For gram-negative organisms and Staphylococcus aureus the Clinical and Laboratory Standards Institute (CLSI) defines MICs of 4 mcg/mL or less as susceptible, 8 mcg/mL as intermediate, and 16 mcg/mL or more that are resistant for gentamicin.
Aminoglycoside resistance is well documented. There are a variety of resistance mechanisms employed by different pathogens. Enzymatic inhibition by gram-negative pathogens and Enterococcus sp. via aminoglycoside-modifying enzymes is achieved by modification of the aminoglycoside as it is transported across the cytoplasmic membrane. Alterations in the inner membrane porin channels by Pseudomonas aeruginosa decrease antimicrobial penetration to the site of activity within the bacterial cell. Some gram-negative organisms and Enterococcus sp. can alter the ribosomal target sites of the aminoglycosides to decrease binding, thereby decreasing antimicrobial activity.
The combination of dexamethasone and tobramycin is administered ophthalmically.
TobraDex ST (tobramycin 0.3%; dexamethasone 0.05%) utilizes a novel suspension technology as compared to TobraDex (tobramycin 0.3%; dexamethasone 0.1%). The xanthan gum in the TobraDex ST product helps reduce settling of the dexamethasone particles in the bottle. There was a 4-fold decrease in the dexamethasone concentration in the TobraDex product as compared to the TobraDex ST product after 24 hours of settling when the bottle was not shaken prior to administration. Additionally, the viscosity of TobraDex ST increases after mixing with tears to allow for longer retention of the formulation in the eye. In vitro studies showed that TobraDex ST viscosity increased 7-fold when mixed with tears, which is approximately 80-fold greater than conventional TobraDex. Animal studies demonstrated an increased bacterial kill rate with TobraDex ST as compared to the conventional product. Additionally, a multi-center, double-masked, parallel-group, randomized, single-dose pharmacokinetic study of 987 cataract surgery patients compared TobraDex (tobramycin 0.3%/dexamethasone 0.1%) to TobraDex ST (tobramycin 0.3%; dexamethasone 0.05%). At 2 hours, the mean dexamethasone concentrations in the aqueous humor were similar with both products (30.9 +/- 16.7 ng/mL for TobraDex and 33.7 +/- 22.8 ng/mL for TobraDex ST).
-Route-Specific Pharmacokinetics
Other Route(s)
Ophthalmic Route
-Tobramycin: Animal data suggest that tobramycin is absorbed into the aqueous humor after topical administration of an ophthalmic solution containing the drug. It is not known whether tobramycin is absorbed into the vitreous humor. Absorption of tobramycin into the aqueous humor is greatest when the cornea is abraded. The manufacturer states that topically administered tobramycin is cleared from the surface of the eye in approximately 15 to 30 minutes when administered as a solution. Information on absorption of tobramycin following administration of an ophthalmic ointment containing the drug is not available.
-Dexamethasone: Following ophthalmic administration, dexamethasone is absorbed through the aqueous humor, with only minimal systemic absorption occurring. Clinical evidence of absorption usually does not occur because topical ophthalmic corticosteroid doses are less than when the drugs are given systemically. The onset of action typically occurs within a few days, but it can take as long as 7 days. Ophthalmic dexamethasone is distributed into local tissues and is metabolized locally.