Tobradex ST

Ophthalmological Corticosteroid and Anti-infective Combinations

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.

ocular hypertension / Delayed / Incidence not known
optic neuritis / Delayed / Incidence not known
erythema multiforme / Delayed / Incidence not known
anaphylactoid reactions / Rapid / Incidence not known
keratitis / Delayed / Incidence not known
nephrotoxicity / Delayed / Incidence not known
ototoxicity / Delayed / Incidence not known

blepharitis / Early / 0-4.0
conjunctival hyperemia / Early / 0-4.0
erythema / Early / 0-4.0
hypertension / Early / 0.5-1.0
impaired wound healing / Delayed / Incidence not known
cataracts / Delayed / Incidence not known
superinfection / Delayed / Incidence not known
ocular infection / Delayed / Incidence not known
bullous rash / Early / Incidence not known
blurred vision / Early / Incidence not known
Cushing's syndrome / Delayed / Incidence not known
neurotoxicity / Early / Incidence not known

ocular pain / Early / 0-4.0
ocular pruritus / Rapid / 0-4.0
headache / Early / 0.5-1.0
infection / Delayed / Incidence not known
pruritus / Rapid / Incidence not known
urticaria / Rapid / Incidence not known
rash / Early / Incidence not known

Tobradex, Tobradex ST

Rx

Topical ophthalmic corticosteroid and aminoglycoside combination
Used for corticosteroid-responsive inflammatory ocular conditions that coexist with superficial bacterial infections
Localized adverse events most common

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.[51765]

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.[51765]

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.[35010]

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.[35010]

0.5 inch ribbon in the affected eye(s) up to 3 to 4 times daily.[40341]

0.5 inch ribbon in the affected eye(s) up to 3 to 4 times daily.[40341]

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.

†Indicates off-label use

No dosage adjustments are needed for ophthalmic topical application.

No dosage adjustments are needed for ophthalmic topical application.

There are no drug interactions associated with Tobramycin; Dexamethasone products.

Tobradex Ophthalmic Ointment: 0.3-0.1%
Tobradex/Tobradex ST/Tobramycin, Dexamethasone Ophthalmic Susp: 0.3-0.05%, 0.3-0.1%

20 mL ophthalmic suspension or 8 g ophthalmic ointment per treatment course.

20 mL ophthalmic suspension or 8 g ophthalmic ointment per treatment course.

20 mL ophthalmic suspension or 8 g ophthalmic ointment per treatment course.

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.

Safety and efficacy have not been established.

Safety and efficacy have not been established.

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).

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.

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.[35010] [40341] [51765]

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.[35010] [40341] [51765] 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.[47299] 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.[27500] 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.