Loteprednol Etabonate/ Tobramycin

Registered South African indications:

• Superficial bacterial ocular infection or where a risk of bacterial ocular infection exists
• 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, and cyclitis
• Chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies

Prescribers must adhere to the principles of antibiotic stewardship. For ophthalmic use only, not for injection into the eye or other tissue.

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of the excipients in this combination product
• Hypersensitivity to other corticosteroids
• Most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment

Precautions for use

• If pain, redness, itching, or inflammation worsens, patients should consult a medical doctor

Avoidance of contact lenses

• Loteprednol etabonate/tobramycin contains benzalkonium chloride; patients should avoid wearing soft contact lenses while using this medication

Benzalkonium chloride considerations

• Benzalkonium chloride may cause eye irritation, dry eye symptoms, and may affect the tear film and corneal surface
• Use with caution in dry eye patients and those with compromised corneas
• Prolonged or repeated use may lead to corneal permeability issues and disruption of the corneal epithelium, requiring regular ophthalmological examinations
• Caution is advised when using benzalkonium chloride-preserved topical medications for an extended period, especially in patients with extensive ocular surface disease

Paediatric population

• Limited data indicate no difference in adverse events between children and adults
• However, children’s eyes may have stronger reactions to stimuli, potentially affecting treatment adherence due to irritation

Intraocular pressure increase

• Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision
• Steroids should be used with caution in patients with glaucoma
• If treatment extends beyond 10 days, intraocular pressure should be monitored regularly

Cataracts

• Use of corticosteroids may result in posterior subcapsular cataract formation

Delayed healing

• The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation
• In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids
• Initial prescription and repeats of the prescription should be made only after examination of the patient with the aid of magnification such as a slit lamp biomicroscopy and, where appropriate, fluorescein staining

Bacterial infections

• Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections
• In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated

Viral infections

• Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution
• Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex)

Fungal infections

• Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application
• Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal cultures should be taken when appropriate

Aminoglycoside hypersensitivity

• Sensitivity to topically applied aminoglycosides may occur in some patients
• Cross-sensitivity to other aminoglycoside antibiotics may also occur, and the possibility that patients who become sensitised to topical ocular tobramycin may also be sensitive to other topical and/or systemic aminoglycosides should be considered
• If hypersensitivity develops with this combination product, discontinue use and institute appropriate therapy

Serum concentration

• Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic aminoglycoside therapy
• If topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics, care should be taken to monitor the total serum concentration
• Caution should be exercised when prescribing loteprednol etabonate/tobramycin 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
• Prolonged use may lead to skin sensitisation or result in overgrowth of non-susceptible organisms, including fungi
• If superinfection occurs, appropriate therapy should be initiated

Ability to drive and use machines

• Loteprednol etabonate/tobramycin may cause blurred vision or other visual disturbances which may affect the ability to drive or use machines. If abnormal or blurred vision occurs at instillation, patients should wait until their vision clears before driving or using machinery

Forms avail. in SA and covered in this monograph: opd

South African registered indications and dosages

Superficial bacterial ocular infection or where a risk of bacterial ocular infection exists
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, and cyclitis
Chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies

Loteprednol Etabonate/ Tobramycin
5/3 (mg/ml)

• Ophthalmic (opd): Usual dose: Apply 1-2 drops into the conjunctival sac of the affected eye(s) every 4-6hrs; Initial 24-48hrs: Dose may be increased to every 1-2hrs; Frequency should be decreased gradually as warranted by improvement in clinical signs; Care should be taken not to discontinue therapy prematurely

---

Shake vigorously before using

---

Prescription guideline
Not more than 20ml should be prescribed initially, and the prescription should not be repeated without further evaluation

---

Handling the container
To avoid contamination, patients should be advised not to let the applicator tip touch the surface of the eye, fingers, or any other surface

No specific recommendation provided

---

From the limited data available, there is no difference in the adverse event profile in children compared to adults. Generally, however, eyes in children show a stronger reaction for a given stimulus than the adult eye. Irritation may have an effect on treatment adherence in children

---

Loteprednol etabonate/tobramycin is not recommended for use in children

Pregnancy

South African recommendations

• Caution; not recommended
• Safety of loteprednol etabonate/tobramycin in pregnancy has not been established
• There are no adequate and well controlled studies of tobramycin in pregnant women
• Teratogenic effects: Loteprednol etabonate has been shown to be embryotoxic and teratogenic when administered to animals
• The potential risk for humans is unknown and loteprednol etabonate/tobramycin should not be used in pregnancy

Breastfeeding

South African recommendations

• Caution; not recommended
• Systemic steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production or cause other untoward effects
• Mothers on treatment with loteprednol etabonate/tobramycin should not breastfeed their babies

Fertility

South African recommendations

• No information available

South African recommendations

• Caution; no information available

South African recommendations

• Caution; no information available

South African recommendations

• No dose adjustment recommended

Loteprednol Etabonate/ Tobramycin

Nervous System Disorders

Common

• Headache

Eye Disorders

Common

• Burning/stinging upon instillation
• Blurred vision
• Conjunctivitis
• Increased lacrimation
• Eye pain
• Meibomianitis
• Corneal staining
• Eyelid erythema
• Eyelid oedema

Uncommon

• Increased intraocular pressure
• Foreign body sensation
• Asthenopia
• Keratitis

Gastrointestinal Disorders

Uncommon

• Nausea

Skin and Subcutaneous Tissue Disorders

Common

• Rash

Loteprednol Etabonate

Eye Disorders

Very common

• Abnormal vision / blurring
• Burning on instillation
• Chemosis
• Discharge
• Dry eye
• Epiphora
• Foreign body sensation
• Itching
• Infection
• Photophobia

Common

• Conjunctivitis
• Corneal abnormalities
• Eyelid erythema
• Keratoconjunctivitis
• Ocular irritation/ pain/ discomfort
• Papillae
• Uveitis

Vascular Disorders

Very common

• Headache

Respiratory, Thoracic and Mediastinal Disorders

Very common

• Rhinitis
• Pharyngitis

Tobramycin

Immune System Disorders

Uncommon

• Hypersensitivity

Nervous System Disorders

Uncommon

• Headache

Eye Disorders

Common

• Ocular discomfort
• Ocular hyperaemia

Uncommon

• Keratitis
• Corneal abrasion
• Visual impairment
• Blurred vision
• Erythema of eyelid
• Conjunctival oedema
• Eyelid oedema
• Eye pain
• Dry eye
• Eye discharge
• Eye pruritis
• Increased lacrimation

Skin and Subcutaneous Tissue Disorders

Uncommon

• Urticaria
• Dermatitis
• Madarosis
• Leukoderma
• Pruritis
• Dry skin

Adverse Reactions observed from Post-marketing Surveillance

Loteprednol Etabonate

Eye Disorders

• Elevated intraocular pressure with damage to the optic nerve
• Visual acuity and field defects
• Posterior subcapsular cataract formation
• Secondary ocular infection
• Perforation of the globe

Tobramycin

Infections and Infestations

• Eye infection (secondary)

Immune System Disorders

• Anaphylactic reaction
• Hypersensitivity (local)

Eye Disorders

• Eye allergy
• Eye irritation
• Ocular hyperaemia
• Blurred vision
• Eyelid oedema
• Eyelids pruritis
• Eye pain (periorbital)

Skin and Subcutaneous Tissue Disorders

• Erythema (periorbital)
• Rash

Loteprednol Etabonate

• Anticholinergic agents (systemically administered)
• Ocular hypotensive agents
• CYP3A inhibitors
• Cobicistat-containing products

Tobramycin

• Neuromuscular blocking agents
• Ototoxic agents
• Carbenicillin

Specific cases may require

• Ophthalmological examination (prolonged use)
• Intraocular pressure (if used for 10 days or longer)
• Total serum concentration (if topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics)

Additional observations

• Eye irritation, symptoms of dry eyes and effects on tear film and corneal surface (in case of prolonged use)

Loteprednol etabonate
Loteprednol etabonate is a corticosteroid. Corticosteroids in vitro inhibit the inflammatory response. Corticosteroids inhibit the inflammatory response to a variety of inciting agents. Corticosteroids inhibit phospholipase A2, an enzyme early in the inflammatory cascade; this inhibition effectively eliminates both cyclooxygenase and lipoxygenase pathways of inflammation. They inhibit the oedema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. While glucocorticoids are known to bind to and activate the glucocorticoid receptor, the molecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation of inflammation are not clearly established. However, corticosteroids are thought to inhibit prostaglandin production through several independent mechanisms.

Tobramycin
Tobramycin is a basic water-soluble aminoglycoside antibiotic, active against most Gram-negative micro-organisms. Tobramycin acts against susceptible bacteria to inhibit protein synthesis and is bactericidal.

Spectrum of activity: Most Gram-negative micro-organisms. Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. Streptococci, including some of the Group A-beta-haemolytic species, some non-haemolytic species, and some Streptococcus pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae, and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species.