Loteprednol; tobramycin is an ophthalmic suspension containing a combination of a corticosteroid (loteprednol) and an aminoglycoside antibacterial (tobramycin). It is indicated for the treatment of steroid-responsive inflammatory ocular conditions where superficial bacterial ocular infection or a risk of bacterial ocular infection exists. Ocular corticosteroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and where the inherent risk of steroid use in certain infective conjunctivitides is accepted to reduce edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies. Tobramycin is active against common bacterial eye pathogens. Loteprednol; tobramycin was approved by the FDA in December 2004.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Ophthalmic Administration
-Loteprednol etabonate; tobramycin ophthalmic suspension is administered topically to the eye. Not for injection into the eye.
-Wash hands before and after use.
-Shake well before use. To avoid contamination, do not to touch the tip of the dropper to the eye, fingertips, or other surface.
-Instruct the patient on proper instillation of eye solution. 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.
-The patient should not wear contact lenses during the treatment course.
In a 42-day safety study comparing loteprednol; tobramycin to placebo, ocular infection occurred in approximately 20% of patients. Secondary ocular infection or superinfection have occurred with the ophthalmic use of either loteprednol or tobramycin from pathogens including viruses such as herpes simplex, fungi, and bacteria. Fungal infections of the cornea may develop during long-term corticosteroid therapy. Fungal invasion should be evaluated in any persistent corneal ulceration where corticosteroid treatment has been used. Fungal cultures may be needed. Additionally, ophthalmic steroid use, such as with loteprednol, may result in delayed or impaired wound healing of the eye or cornea following injury or surgery, or mask the signs of ocular infection.
In a 42-day safety study, increased intraocular pressure (ocular hypertension) was reported in 10% of patients who received loteprednol; tobramycin, compared to 4% who received placebo. In general, prolonged ophthalmic steroid use may result in increased intraocular pressure with the potential to worsen glaucoma and cause optic nerve damage. Loteprednol is associated with a lower incidence of increased intraocular pressure compared to prednisolone, a more potent ophthalmic steroid. In large controlled clinical trials of prednisolone acetate 1% versus loteprednol 0.2 to 0.5%, ocular administration for 28 days or longer resulted in significant elevation of intraocular pressure (IOP 10 mmHg or greater) in 2% of loteprednol recipients versus 7% with prednisolone and 0.5% with placebo. Increased intraocular pressure due to corticosteroid use may be associated with optic nerve damage (infrequent) or visual impairment including defects in visual acuity and visual fields. In patients with corneal or scleral thinning, administration of topical ophthalmic corticosteroids has caused globe perforation. Increased ocular pressure can occur in normal and glaucomatous eyes and usually develops 2 to 8 weeks after initiating ophthalmic steroid use. Ocular hypertension is generally reversible 1 to 3 weeks after steroid discontinuation; however, persistent pressure elevation with glaucoma and vision loss has occurred. Intraocular pressure elevations are usually greater in eyes with open-angle glaucoma. Monitor intraocular pressure if loteprednol is used for longer than 10 days.
In a 42-day safety study comparing loteprednol; tobramycin to placebo, superficial punctate keratitis was reported in approximately 15% of patients. Ocular irritation or ocular pain on administration, reported as burning and stinging, occurred in 9%. Adverse ocular reactions reported with an incidence of less than 4% include vision disorders, ocular discharge, ocular pruritus, lacrimation disorder, photophobia, corneal deposits, ocular discomfort, eyelid disorder, and other unspecified eye disorders. Of note, the most frequent adverse reactions to topical tobramycin are hypersensitivity and localized ocular toxicity, including lid itching, blepharitis, and conjunctival erythema (conjunctivitis), occurring in less than 4% of patients.
In a 42-day safety study comparing loteprednol; tobramycin to placebo, headache was reported in approximately 14% of patients. Other non-ophthalmic reactions had an incidence of less than 5%, but were not specified.
Long-term ocular administration of corticosteroids, such as loteprednol, over several years has been associated with the formation of posterior subcapsular cataracts. Patients should be monitored for the development of lens opacities during prolonged corticosteroid use.
Tobramycin should not be used in patients with a history of aminoglycoside hypersensitivity. Cross-sensitivity with other aminoglycoside antibiotics may occur. Loteprednol may mask signs and symptoms of tobramycin hypersensitivity. Loteprednol is also contraindicated in individuals with glycerin hypersensitivity or hypersensitivity to loteprednol, corticosteroid hypersensitivity, or sensitivity to any of the other product ingredients (edetate disodium, povidone, tyloxapol, and benzalkonium chloride). If hypersensitivity develops, discontinue use and institute appropriate therapy.
The use of ocular steroids may prolong the course and exacerbate the severity of ocular infections. Ophthalmic steroid use may result in delayed or impaired wound healing of the eye or cornea, or mask the signs of ocular infection. Loteprednol, as with other ophthalmic corticosteroids, is contraindicated in most cases of viral infection of the cornea and conjunctiva including herpes infection, such as herpes simplex virus epithelial keratitis, and varicella. Loteprednol is also contraindicated in mycobacterial infection of the eye and fungal infection of ocular structures. Fungal infections of the cornea may develop with long-term ocular application of steroids. Fungal invasion should be evaluated in any persistent corneal ulceration where corticosteroid treatment has been used. Fungal cultures should be taken when appropriate. Corticosteroid therapy can also exacerbate purulent bacterial infections of the eye. If signs and symptoms do not improve or appear to worsen, loteprednol; tobramycin therapy should be reevaluated.
Intraocular hypertension is most likely to occur in patients receiving prolonged ophthalmic corticosteroids and in patients with glaucoma. Intraocular pressure elevations are usually greater in eyes with open-angle glaucoma. If loteprednol etabonate is used for 10 days or longer, intraocular pressure should be monitored. If ocular signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. Regular ophthalmic examinations are recommended after 14 days of loteprednol and tobramycin therapy to identify corneal abnormalities, lens opacities, and increased intraocular pressure (IOP). Periodic slit-lamp examinations for punctate, herpetic, or fungal keratitis is necessary. Where appropriate, fluorescein staining should be done.
Long-term ocular administration of corticosteroids for several years has been associated with the formation of posterior subcapsular (PSC) cataracts. Patients with diabetes mellitus appear to be more susceptible to developing PSC cataracts during ocular steroid use. Patients should be monitored for the development of lens opacities during long-term loteprednol and tobramycin therapy. The use of steroids immediately after cataract surgery may delay healing and increase the incidence of bleb formation. Use loteprednol; tobramycin with caution in patients who have had cataracts recently removed.
In patients with corneal or scleral thinning, administration of topical ophthalmic corticosteroids have caused perforations. Loteprednol; tobramycin should be used with caution in patients with a corneal abrasion.
Patients should not wear contact lenses when using loteprednol; tobramycin. Patients who wear contact lenses should be aware that benzalkonium chloride, a preservative in loteprednol; tobramycin can be absorbed by soft contact lenses.
There are no adequate and well-controlled studies regarding the use of loteprednol etabonate; tobramycin during pregnancy. In animal studies involving pregnant rabbits and rats, loteprednol produced teratogenicity at clinically relevant doses when administered orally during pregnancy. Loteprednol produced malformations at oral doses of 0.54 to more than 13 times the recommended human ophthalmic dose (RHOD), assuming 100% absorption. Observed malformations in rabbit studies included spina bifida (including meningocele), exencephaly, craniofacial malformations, abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, and delayed ossification. In studies involving pregnant rats, observed malformations included absent innominate artery, cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight, and decreased skeletal ossification. At doses administered in animal studies during the equivalent to the last trimester of pregnancy through lactation in humans, survival of offspring was reduced at doses at least 1.3 times the RHOD. Abortion and embryofetal lethality (resorption) occurred and doses 32 to 270 times the RHOD. Maternal toxicity was observed at doses at least 135 times the RHOD, and a maternal no observed adverse effect level (NOAEL) was established at 13 times the RHOD. For tobramycin used in animal studies, abortions were observed when tobramycin was administered via subcutaneous injection at doses 180 times the RHOD. The developmental and maternal NOAEL for tobramycin was 450 times the RHOD. Although loteprednol etabonate; tobramycin is not significantly absorbed following ophthalmic administration with plasma concentrations less than 1 ng/mL, the drug should be used during pregnancy only if the potential benefits outweigh the risks of therapy. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration.
There are no data on the presence of loteprednol; tobramycin in human breast milk, the effects on the breastfed infant, or the effects on milk production. However, pharmacokinetic studies indicate that loteprednol is not significantly absorbed following ophthalmic administration with plasma concentrations less than 1 ng/mL, 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. The American Academy of Pediatrics (AAP) did not evaluate loteprednol in breast-feeding mothers; however, previous AAP recommendations considered the corticosteroids prednisone and prednisolone to be usually compatible with lactation. Aminoglycosides are generally excreted into breast milk in low concentrations. However, they are poorly absorbed from the gastrointestinal tract are not likely to cause adverse events in nursing infants. Tobramycin breast milk concentrations after systemic administration are around 0.52 mcg/mL. Previous AAP recommendations considered several aminoglycosides to be compatible with breast-feeding. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition.
Safety and efficacy of loteprednol; tobramycin ophthalmic suspension in neonates, infants, children, and adolescents have not been established. Two trials have been conducted to evaluate the safety and efficacy in pediatric patients aged 0 to 6 years. In the first trial, patients with lid inflammation received either loteprednol; tobramycin with warm compresses or vehicle only with warm compresses. The results failed to show increased efficacy with active treatment, as the majority of patients in both treatment groups demonstrated reduced lid inflammation. In the second trial, patients with blepharoconjunctivitis were treated with either loteprednol; tobramycin, vehicle only, loteprednol ophthalmic suspension, or tobramycin ophthalmic suspension. Data from this trial also failed to show increased efficacy with the combination product. There was no difference in safety between the treatment groups in either trial.
No overall differences in safety and efficacy of loteprednol; tobramycin have been observed between geriatric and younger adult patients. However, elderly patients may have pre-existing conditions such as glaucoma, increased intraocular pressure, and diabetes mellitus.
Loteprednol; tobramycin may be associated with reproductive risk. In animal studies with oral loteprednol treatment, using a dose 67 times the recommended human ophthalmic dose (RHOD), prior to and during mating caused preimplantation loss and decreased number of live fetuses/live births. However, pharmacokinetic studies indicate that loteprednol is not significantly absorbed following ophthalmic administration with plasma concentrations less than 1 ng/mL.
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 a superficial bacterial ophthalmic infection or a risk of bacterial infection exists, including 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 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 (loteprednol etabonate 0.5% and tobramycin 0.3% 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 1 to 2 hours if needed for the first 24 to 48 hours. Reduce dose gradually as warranted by clinical improvement.
-for the treatment of dry eye disease with known or suspected ophthalmic infection:
Ophthalmic dosage (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension):
Adults: 1 to 2 drops in each eye 4 times daily, initially. Reduce dose to 1 to 2 drops 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
24 drops/day loteprednol 0.5% and tobramycin 0.3% in the affected eye(s).
-Geriatric
24 drops/day loteprednol 0.5% and tobramycin 0.3% in the affected eye(s).
-Adolescents
Safety and efficacy have not been established.
-Children
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 adjustment is needed.
Patients with Renal Impairment Dosing
No dosage adjustment is needed.
*non-FDA-approved indication
There are no drug interactions associated with Loteprednol; Tobramycin products.
Mechanism of Action:-Loteprednol: Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure.
-Tobramycin: Tobramycin is a bactericidal aminoglycoside antibiotic. 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. The uptake of aminoglycosides may be facilitated by the presence of inhibitors of the bacterial cell wall.
Loteprednol; tobramycin is administered topically to the eye. The pharmacokinetics of this drug combination have not been studied. The pharmacokinetic information below is based on administration of each agent alone.
-Loteprednol: Loteprednol etabonate is lipid soluble and can penetrate into cells. Loteprednol etabonate undergoes a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites, PJ-91 and PJ-90.
-Tobramycin: Tobramycin distributes into extracellular fluid; therefore, peak serum concentrations may be lower in patients with a large volume of extracellular fluid. The volume of distribution may be higher in patients with sepsis, fever, severe burns, congestive cardiac failure, and peritonitis, which may result in lower peak concentrations. Protein binding of tobramycin is negligible. After administration, tobramycin can be detected in sputum, peritoneal fluid, synovial fluid, and abscess fluid. Tobramycin appears in low concentrations in the CSF, and concentrations are dependent on dose, rate of penetration, and degree of meningeal inflammation.
Affected cytochrome P450 isoenzymes and drug transporters: None
-Route-Specific Pharmacokinetics
Other Route(s)
Ophthalmic Route
The ocular concentration of loteprednol in combination with tobramycin was found to be comparable to the concentration of loteprednol alone. Loteprednol penetration into the eye is neither increased or decreased with the addition of tobramycin to the preparation.
-Loteprednol: Limited systemic absorption (less than 1 ng/mL) of loteprednol 0.5% occurs following daily administration. Bioavailability data in normal volunteers receiving 0.5% loteprednol etabonate 8 times daily for 2 days or 4 times daily for 42 days demonstrated insignificant plasma concentrations of loteprednol etabonate and its primary carboxylic acid metabolite at all sampling times.
-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.