Zylet

Ophthalmological Corticosteroid and Anti-infective Combinations

Zylet (0.5% loteprednol etabonate and 0.3% 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—2 minutes. Do not blink.
The patient should not wear contact lenses during the treatment course.

keratitis / Delayed / 15.0-15.0
ocular hypertension / Delayed / 10.0-10.0
visual impairment / Early / Incidence not known

ocular infection / Delayed / 20.0-20.0
corneal deposits / Delayed / 0-4.0
photophobia / Early / 0-4.0
impaired wound healing / Delayed / Incidence not known
superinfection / Delayed / Incidence not known
blepharitis / Early / Incidence not known
conjunctivitis / Delayed / Incidence not known
cataracts / Delayed / Incidence not known

headache / Early / 14.0-14.0
ocular irritation / Rapid / 0-4.0
ocular discharge / Delayed / 0-4.0
ocular pain / Early / 0-4.0
ocular pruritus / Rapid / 0-4.0

Zylet

Rx

Ophthalmic suspension of a corticosteroid (loteprednol) plus aminoglycoside antibiotic (tobramycin); indicated for steroid-responsive inflammatory conditions associated with superficial bacterial ocular infection or a risk thereof.

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. 

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.

No dosage adjustment is needed.

No dosage adjustment is needed.

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

Zylet Ophthalmic Susp: 0.5-0.3%

24 drops/day loteprednol 0.5% and tobramycin 0.3% in the affected eye(s).

24 drops/day loteprednol 0.5% and tobramycin 0.3% in the affected eye(s).

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Mechanism of Action:•Loteprednol: Corticosteroids inhibit 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 control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the precursor molecule arachidonic acid. Corticosteroids inhibit edema, fibrin deposition, capillary dilatation, and migration of leukocytes and phagocytes in the acute inflammatory response. They may also reduce capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation. They also inhibit the body's immune response against infection and reduce the outflow of aqueous humor, thereby increasing intraocular pressure and inducing or aggravating open-angle glaucoma.•Tobramycin: Tobramycin is a bactericidal aminoglycoside antibiotic. It binds irreversibly to one of two aminoglycoside binding sites on the 30 S ribosomal subunit and inhibits bacterial protein synthesis. However, inhibition of bacterial protein synthesis does not adequately explain tobramycin's bactericidal effects, since other non-aminoglycoside antibiotics that also inhibit protein synthesis are only bacteriostatic. 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 combination of loteprednol and 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: Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism (primarily by hydrolysis) to inactive carboxylic acid metabolites.

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 (< 1 ng/ml) absorption of loteprednol occurs following daily administration. Bioavailability data in normal volunteers receiving 0.5% loteprednol etabonate eight times daily for 2 days or four times daily for 42 days demonstrated insignificant plasma levels 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. One manufacturer of tobramycin states that topically administered tobramycin is cleared from the surface of the eye in approximately 15—30 minutes when administered as a solution.

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.