Treatment of post-operative inflammation and pain following ocular surgery.

Posology

One to two drops into the conjunctival sac of the affected eye four times daily beginning the day after surgery and continuing throughout the first 2 weeks of the post-operative period. 

Method of administration 
Ocular administration. 
Invert closed bottle and shake once to fill tip before instilling drops. 
If another topical ophthalmic medicinal product is being used, the medicines should be administered at least ten minutes apart. Eye ointments or gels should be administered last. 

This product is a sterile preserved ophthalmic gel. It can be used only if imprinted neckband is intact. Patients should be instructed to wash their hands before use and avoid allowing the dropper tip to contact the eye, surrounding structures and any other surface. 
Patients should also be instructed that ophthalmic medicinal products, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated gels. If pain develops, redness, itching or inflammation becomes aggravated, the patient should be advised to consult a physician.  

As with other ophthalmic preparations containing benzalkonium chloride, patients should be advised not to wear soft contact lenses when using Lotemax. The bottle should be closed immediately after use. 

Hypersensitivity to the active substance, to other corticosteroids or to any of the excipients listed in section 6.1. As with other ophthalmic corticosteroids, Lotemax is also 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.

Not for injection into the eye. 
Intraocular Pressure (IOP) Increase 
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. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored. 

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. The initial prescription and renewal of the medication order 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. 

Bacterial Infections 
Prolonged use of corticosteroids may suppress the host response and thus may increase the possibility 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. 

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 the differential diagnosis in any persistent corneal ulceration where a steroid has been used or is in use. Fungal cultures should be taken when appropriate. 

Contact Lens Wear 
Patients should not wear contact lenses during their course of therapy with Lotemax. 
Lotemax contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. 
Special populations 
No overall differences in safety and effectiveness have been observed between elderly and younger patients. 

Nonclinical studies in rabbits indicate that the ocular disposition of loteprednol etabonate is not substantially altered by administration with other drugs, including tobramycin. However, no in vitro studies have been conducted to assess the potential for pharmacokinetic drug interactions. Specifically, the effect of loteprednol etabonate on the inhibition or induction of cytochrome P450 enzymes has not been investigated. 
Since loteprednol etabonate is not detected in plasma following the topical administration of LOTEMAX, it is not expected to affect the pharmacokinetics of systemically administered medicinal products. 
However, the low potential of ocular loteprednol etabonate eye gel 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. 

Pregnancy 
Teratogenic Effects: 
There are no adequate and well controlled studies in pregnant women. However, studies in animals have  shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown, therefore Lotemax should not be used in pregnancy unless clearly necessary.  

Breastfeeding 
It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when LE is administered to a  nursing woman. 
Fertility 
Animal reproductive studies of loteprednol etabonate have revealed no evidence of impairment fertility (see section 5.3). 

No studies on the effects on the ability to drive and use machines after instillation have been performed. 
However, as all products administered to eye, it may cause transient blurred vision, which may impair the ability to drive or to use machinery, especially at night or in reduced lighting. The patient should wait until these symptoms have cleared before driving or using machinery. 

Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. 
In clinical studies with loteprednol etabonate ophthalmic gel (LE gel), the most common reported ocular adverse drug reactions were: anterior chamber inflammation, eye pain and foreign body sensation 

Adverse reactions	LE gel (N=409)	Placebo (N=404)
Eye disorders Anterior chamber inflammation Eye pain  Photophobia  Foreign body sensation in eyes  Iritis  Conjunctival haemorrhage Lacrimation increased	3.7% 2.0% 1.2% 2.0% 1.0% 1.2% 1.5%	5.9% 4.5% 3.0% 2.0% 1.2% 0.2% 0.0%

To report any side effect(s):

Saudi Arabia:

-    The National Pharmacovigilance and Drug Safety Centre (NPC)
•    Fax:  +966-11-205-7662
•    Call NPC at +966-11-2038222, Exts:  2317-2356-2353-2354-2334-2340.
•    Toll free phone: 8002490000
•    Reporting hotline: 19999
•    E-mail: npc.drug@sfda.gov.sa
•    Website:  www.sfda.gov.sa/npc

Other GCC States: Please contact the relevant competent authority.

Acute overdosage is unlikely to occur via the ophthalmic route. Particularly with the use of topical gel.

Pharmacotherapeutic group: Corticosteroids, ATC code: S01BA14 
Mechanism of action 
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. 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. 

Loteprednol etabonate is a new class of corticosteroid with potent antiinflammatory activity designed to be active at the site of action. Its antiinflammatory activity is similar to the most powerful steroid used in ophthalmology but with less intraocular pressure. Receptor binding studies have shown that loteprednol etabonate has a binding affinity to steroid receptors that is 4.3 times greater than dexamethasone and that binds competitively to transcortin, a corticosteroid-binding plasma protein.  Loteprednol etabonate is structurally similar to other corticosteroids. However, unlike other corticosteroids loteprednol etabonate is an ester rather than a ketone (position 20). This new class of steroids consists of bioactive molecules whose in-vivo transformation to non-toxic substances can be predicted from their chemistry and knowledge of enzymatic pathways in the body. 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. 

Clinical efficacy and safety 

In two randomized, multicenter, double-masked, parallel-group, placebo-controlled studies in 813 adult subjects (409 subjects treated with Lotemax gel and 404 treated with placebo) with, post-operative inflammation, Lotemax was more effective compared to its vehicle as a placebo in resolving anterior chamber inflammation and pain following cataract surgery. Primary endpoints were complete resolution of anterior chamber cells (cell count of 0) and no pain at post-operative day 8. In these studies, Lotemax had a statistically significant higher incidence of subjects with complete clearing of anterior chamber cells (31% vs. 14-16%) and were pain free at post-operative day 8 (73-76% vs. 42-46%). 

The safety and effectiveness of Lotemax were evaluated in a pediatric study of patients from birth to less than 11 years of age (mean age of 3 years) undergoing cataract surgery. Patients were randomized, to receive either Lotemax (54 patients) or prednisolone acetate ophthalmic suspension 1% (53 patients) four times a day for 14 days. At Day 14, the percentages of patients with complete clearing of anterior chamber inflammation were 57% in the Lotemax group and 63% in the prednisolone group. 

Loteprednol is lipid soluble and can penetrate into cells. 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 studies loteprednol etabonate undergoes extensive metabolism to the inactive carboxylic acid metabolites, PJ-91 and PJ-90. Results from the nonclinical evaluation of LE demonstrate that it is rapidly absorbed into ocular tissues with minimal (eg, <1 ng/mL) systemic exposure following topical ocular administration. The systemic exposure to loteprednol etabonate following ocular administration of Lotemax has not been studied in humans. 

Non-clinical data reveal no special hazard for humans based on conventional studies of repeated dose and genotoxicity. 
Carcinogenic potential 
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate. 
Genotoxicity 
Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma TK assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay. 

Reproductive toxicity 
Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery, and limb flexures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (35 times the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (6 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at ≥5 mg/kg/day doses, and cleft palate and umbilical hernia at 
≥50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day (6 times the maximum clinical dose) during organogenesis did not result in any reproductive toxicity. 
Loteprednol etabonate was maternally toxic (significantly reduced body weight gain during treatment) when administered to pregnant rats during organogenesis at doses of ≥5 mg/kg/day. 
Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from the start of the fetal period through the end of lactation, a maternally toxic treatment regimen (significantly decreased body weight gain), gave rise to decreased growth and survival, and retarded development in the offspring during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol etabonate had no effect on the duration of gestation or parturition when administered orally to pregnant rats at doses up to 50 mg/kg/day during the fetal period. 
Fertility 
Treatment of male and female rats with up to 50 mg/ kg/day and 25 mg/kg/day of loteprednol etabonate, respectively prior to and during mating did not impair fertility in either gender. 

Edetate Disodium 
Dihydrate Glycerin 
Propylene 
Glycol Boric 
Acid 
Polycarbophil 
Sodium 
Chloride 
Tyloxapol 
Sodium Hydroxide to adjust to a pH of between 6 and 7 
Benzalkonium  Chloride (0.003%) 
Water for injection 

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

Un opened: 2 years The in-use shelf-life is 28 days from opening date.

Do not store above 25 C. Do not Freeze. 
Store the container in upright position. 

Lotemax 0.5% ophthalmic gel is available in the following  packaging configurations:

5 g in a 10 ml white low density polyethylene (LDPE) bottle with a white LLDPE controlled drop tip, and a pink polypropylene cap

Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 
Use only if imprinted neckband is intact.