Composition

Loteprednol Etabonate……… 5 mg (0.5%)

Benzalkonium Chloride……...0.01%

Sterile aqueous vehicle……….q.s

Corticosteroids inhibit the inflammatory response to a variety of inciting agents of mechanical, chemical or immunological nature 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 (IOP).

Loteprednol etabonate is class of corticosteroid with potent anti-inflammatory activity designed to be active at the site of action. Its anti-inflammatory activity is similar to the most powerful steroid used in ophthalmology but with less intraocular pressure. Loteprednol etabonate is structurally similar to other corticosteroids. However, the number 20 position ketone group is absent. It is highly lipid soluble which enhances its penetration into cells. Animal studies have shown that loteprednol etabonate has a binding affinity to steroid receptors that is 4.3 times greater than dexamethasone. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo 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.

Cortienic acid is an inactive metabolite of hydrocortisone and analogs of cortienic acid are also devoid of corticosteroid activity. Loteprednol etabonate is an ester derivative of one of these analogs, cortienic acid etabonate.

Placebo controlled studies demonstrated that loteprednol etabonate is significantly more effective than placebo for the treatment of external ocular inflammation.

Corticosteroids are capable of producing a rise in intraocular pressure in susceptible individuals. In a small study, loteprednol etabonate ophthalmic suspension demonstrated a significantly longer time to produce a rise in pressure than did prednisolone acetate. The overall incidence of patients who had an intraocular pressure elevation of 10 mm Hg was lower in the loteprednol treated patients. In many patients treated with loteprednol the ultimate rise in intraocular pressure never achieved the levels seen in patients treated with prednisolone acetate. In clinical trials only 2% of all patients had an intraocular pressure elevation of 10 mm Hg. In the small percentage of patients who did show a significant rise in intraocular pressure, pressure rapidly returned to normal on discontinuation of the medicinal products.

Clinical Studies

Post-Operative Inflammation: Placebo-controlled clinical studies demonstrated that loteprednol etabonate ophthalmic suspension is effective for the treatment of anterior chamber inflammation as measured by cell and flare.

Giant Papillary Conjunctivitis: Placebo-controlled clinical studies demonstrated that loteprednol etabonate ophthalmic suspension was effective in reducing the signs and symptoms of giant papillary conjunctivitis after 1 week of treatment and continuing for up to 6 weeks while on treatment.

Seasonal Allergic Conjunctivitis: A placebo-controlled clinical study demonstrated that loteprednol etabonate ophthalmic suspension was effective in reducing the signs and symptoms of allergic conjunctivitis during peak periods of pollen exposure.

Uveitis: Controlled clinical studies of patients with uveitis demonstrated that loteprednol etabonate ophthalmic suspension was less effective than prednisolone acetate 1%. Overall, 72% of patients treated with loteprednol experienced resolution of anterior chamber cell by day 28, compared to 87% of patients treated with 1% prednisolone acetate. The incidence of patients with clinically significant increases in IOP (≥10 mmHg) was 1% with loteprednol and 6% with prednisolone acetate 1%.

Loteprednol etabonate should not be used in patients who require a more potent corticosteroid for this indication.

Pharmacokinetics

Results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and (DELTA)¹cortienic acid etabonate (PJ 91), its primary, inactive metabolite, were below the limit of quantitation (1 ng/mL) at all sampling times. The results were obtained following the ocular administration of one drop in each eye of 0.5% loteprednol etabonate 8 times daily for 2 days or 4 times daily for 42 days. This study suggests that limited (<1 ng/ml) systemic absorption occurs with loteprednol etabonate ophthalmic suspension.

Indications

Loteprednol etabonate 0.5% ophthalmic suspension is indicated for the treatment of steroid responsive 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, selected infective conjunctivitides, when the inherent hazard of steroid use is accepted to obtain an advisable diminution in edema and inflammation.

Loteprednol etabonate 0.5% ophthalmic suspension is also indicated for the treatment of post-operative inflammation following ocular surgery.

Dosage and Administration

SHAKE VIGOROUSLY BEFORE USING.

Steroid Responsive Disease Treatment

Apply one to two drops of LOTEFLAM ophthalmic suspension into the conjunctival sac of the affected eye(s) four times daily. During the initial treatment within the first week, the dosing may be increased, up to 1 drop every hour, if necessary. Care should be taken not to discontinue therapy prematurely. If signs and symptoms fail to improve after two days, the patient should be re-evaluated.

Post-Operative Inflammation

Apply one to two drops of LOTEFLAM ophthalmic suspension into the conjunctival sac of the operated eye(s) four times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the post-operative period.

The duration of treatment should not exceed 2 weeks.

Contraindications

Loteprednol etabonate ophthalmic suspension, as with other ophthalmic corticosteroids, is contraindicated in 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; untreated purulent acute infections which, similar to other infectious diseases, can be masked and worsened by corticoids, 'red eye' with unknown diagnosis and infection caused by amoeba.

Loteprednol etabonate ophthalmic suspension is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation or to other corticosteroids.

Warnings and Precautions

General

For ophthalmic use only.

Prolonged use of corticosteroids may result in ocular hypertension or glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Steroids should be used with caution in the presence of glaucoma.

Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection.

Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation.

The initial prescription and renewal of the medication order beyond 14 days should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.

If signs and symptoms fail to improve after two days, the patient should be re-evaluated.

If this product is used for 10 days or longer, intraocular pressure should be monitored even though it may be difficult in children and uncooperative patients.

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.

LOTEFLAM ophthalmic suspension contains benzalkonium chloride which may cause eye irritation.

Effect on Ability to Drive and Use Machines

No studies on the effects on the ability to drive and use machines have been performed.

If there are any transient effects on vision, the patient should be advised to wait until these subside before driving or operating machinery.

Drug Interactions

Since loteprednol etabonate is not detected in plasma following the topical administration of loteprednol etabonate ophthalmic suspension, it is not expected to affect the pharmacokinetics of systemically administered medicinal products. However, the low potential of ocular loteprednol etabonate eye drops to increase the intraocular pressure may be adversely affected by systemically administered medicinal products with anticholinergic activity. In patients receiving concomitant ocular hypotensive therapy, the addition of loteprednol etabonate may increase intraocular pressure and decrease the apparent ocular hypotensive effect of these medicinal products.

Concurrent administration of cycloplegics may increase the risk of raised intraocular pressure.

Co-treatment with CYP3A inhibitors, including cobicistat-containing products, is expected to increase the risk of systemic side-effects. The combination should be avoided unless the benefit outweights the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.

Pregnancy

Teratogenic Effects

Pregnancy Category C

There are no adequate and well-controlled studies of loteprednol etabonate in pregnant women, and it is not known whether loteprednol etabonate can cause fetal harm when administered to a pregnant woman. Loteprednol etabonate ophthalmic suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when LOTEFLAM ophthalmic suspension is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Undesirable Effects

Reactions associated with ophthalmic steroids include elevated intraocular pressure in steroid responsive patients, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.

Ocular adverse reactions occurring in 5-15% of patients treated with loteprednol etabonate ophthalmic suspension (0.2%-0.5%) in clinical studies included abnormal vision/blurring, burning on instillation, chemosis, corneal defect, conjunctival hyperemia, discharge, dry eyes, epiphora, foreign body sensation, itching, injection, and photophobia. Other ocular adverse reactions occurring in less than 5% of patients include conjunctivitis, corneal abnormalities, eyelid erythema, keratoconjunctivitis, ocular irritation/pain/discomfort, conjunctival papillae, iritis and uveitis. Some of these events were similar to the underlying ocular disease being studied.

Non-ocular adverse reactions occurred in less than 15% of patients. These include headache, rhinitis and pharyngitis.

Ocular adverse reactions occurring in patients treated with loteprednol etabonate ophthalmic suspension in clinical studies included the following:

All undesirable effects have been classified as follows very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10,000, <1/1000), or very rare (<1/10,000).

Eye Disorders

Common: Corneal defects, eye discharge, ocular discomfort, dry eye, epiphora, foreign body sensation in eyes, conjunctival hyperemia and ocular itching.

Uncommon: Abnormal vision, chemosis, keratoconjunctivitis, conjunctivitis, iritis, eye irritation, eye pain, conjunctival papillae, photophobia and uveitis.

Not known: vision blurred

Some of these events were similar to the underlying ocular disease being studied.

Non-ocular events possibly related to treatment occurring in patients included:

Nervous system disorders

Common: Headache

Rare: Migraine, taste perversion, dizziness, paresthesia

General Disorders and Administration Site Conditions

Uncommon: Asthenia

Rare: Chest pain, chills, fever and pain

Respiratory, Thoracic and Mediastinal Disorders

Uncommon: Rhinitis

Rare: Cough

Infections and Infestations

Uncommon: Pharyngitis

Rare: Urinary tract infection and urethritis

Skin and Subcutaneous Tissue Disorders

Rare: Face oedema, urticaria, rash, dry skin and eczema

Gastrointestinal Disorders

Rare: Diarrhoea, nausea and vomiting

Investigations

Rare: Weight gain

Ear and Labyrinth Disorders

Rare: Tinnitus

Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps)

Rare: Breast neoplasm

Musculoskeletal and Connective Disorders

Rare: Twitching

Psychiatric Disorders

Rare: Nervousness

In a summation of controlled, randomized studies of individuals treated for 28 days or longer with loteprednol etabonate, the incidence of significant elevation of intraocular pressure ≥ 10 mmHg) was 2% (15/901) among patients receiving loteprednol etabonate, 7% (11/164) among patients receiving 1% prednisolone acetate and 0.5% (3/583) among patients receiving placebo.

Overdosage

No case of overdose has been reported. Acute overdosage is unlikely to occur via the ophthalmic route.

Incompatibility

In the absence of incompatibility studies, this medicinal product should not be mixed with other medicinal products.

Shelf-Life

2 years

Storage and Handling Instructions

Store upright between 15°-25°C (59°-77°F) DO NOT FREEZE.

Packaging Information

LOTEFLAM Eye Drops: Vial of 5 ml

Information for Patients

Shake the bottle vigorously before using the eye drops. This product is sterile when packaged. Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the suspension. If pain develops, redness, itching or inflammation becomes aggravated; the patient should be advised to consult a physician.

As with all ophthalmic preparations containing benzalkonium chloride, patients should be advised not to wear soft contact lenses when using LOTEFLAM ophthalmic suspension.

In general patients should not wear contact lenses after cataract surgery, unless contact lens wearing is medically indicated. Patients should be advised to remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Known to discolour soft contact lenses.

Last Updated: December 2018

Last Reviewed: December 2018

LOTEFLAM Eye Drops