Lotinil (loteprednol etabonate and tobramycin ophthalmic suspension), 0.5%/0.3% is a topical
anti-infective and corticosteroid combination for steroid-responsive inflammatory ocular
conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection
or a risk of bacterial ocular infection exists.
Ocular steroids 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 obtain a diminution in 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.
The use of a combination drug with an anti-infective component is indicated where the risk of
superficial ocular infection is high or where there is an expectation that potentially dangerous
numbers of bacteria will be present in the eye.
The particular anti-infective drug in this product (tobramycin) is active against the following
common bacterial eye pathogens:
Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative),
including penicillin-resistant strains. Streptococci, including some of the Group A-beta-hemolytic
species, some nonhemolytic 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.

Apply one or two drops of Lotinil into the conjunctival sac of the affected eye every four to six hours.
During the initial 24 to 48 hours, the dosing may be increased, to every one to two hours. Frequency should
be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to
discontinue therapy prematurely.

Lotinil, as with other steroid anti-infective ophthalmic combination drugs, 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.

Intraocular Pressure (IOP) 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 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 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. If hypersensitivity
develops with this product, discontinue use and institute appropriate therapy.
Risk of Contamination
Do not allow the dropper tip to touch any surface, as this may contaminate the suspension.
Contact Lens Wear
As with all ophthalmic preparations containing benzalkonium chloride, patients should be advised
not to wear soft contact lenses when using Loteprednol Etabonate and Tobramycin Ophthalmic
Suspension.

Adverse reactions have occurred with steroid/anti-infective combination drugs which can be
attributed to the steroid component, the anti-infective component, or the combination.
In a 42-day safety study comparing Loteprednol Etabonate and Tobramycin Ophthalmic Suspension
to placebo, ocular adverse reactions included injection (approximately 20%) and superficial punctate
keratitis (approximately 15%). Increased intraocular pressure was reported in 10% (Loteprednol
Etabonate and Tobramycin Ophthalmic Suspension) and 4% (placebo) of subjects. Nine percent
(9%) of Loteprednol Etabonate and Tobramycin Ophthalmic Suspension subjects reported burning
and stinging upon instillation.
Ocular reactions reported with an incidence less than 4% include vision disorders, discharge, itching,
lacrimation disorder, photophobia, corneal deposits, ocular discomfort, eyelid disorder, and other
unspecified eye disorders.
The incidence of non-ocular reactions reported in approximately 14% of subjects was headache; all
other non-ocular reactions had an incidence of less than 5%.
Loteprednol etabonate ophthalmic suspension 0.2% - 0.5%
Reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be
associated with infrequent 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 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 mm Hg)
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.

Tobramycin ophthalmic solution 0.3%
The most frequent adverse reactions to topical tobramycin are hypersensitivity and localized ocular
toxicity, including lid itching and swelling and conjunctival erythema. These reactions occur in less
than 4% of patients. Similar reactions may occur with the topical use of other aminoglycoside
antibiotics.
Secondary Infection
The development of secondary infection has occurred after use of combinations containing steroids
and antimicrobials. Fungal infections of the cornea are particularly prone to develop coincidentally
with long-term applications of steroids.
The possibility of fungal invasion must be considered in any persistent corneal ulceration where
steroid treatment has been used.
Secondary bacterial ocular infection following suppression of host responses also occurs.

Pregnancy
Risk Summary
There are no adequate and well-controlled studies with loteprednol etabonate or tobramycin in
pregnant women.
Loteprednol etabonate produced teratogenicity at clinically relevant doses in the rabbit and rat when
administered orally during pregnancy. Loteprednol etabonate produced malformations when
administered orally to pregnant rabbits at doses ≥ 0.54 times the recommended human ophthalmic
dose (RHOD) and to pregnant rats at doses ≥ 13 times the RHOD. In pregnant rats receiving oral
doses of loteprednol etabonate during the period equivalent to the last trimester of pregnancy through
lactation in humans, survival of offspring was reduced at doses ≥ 1.3 times the RHOD. Maternal
toxicity was observed in rats at doses ≥ 135 times the RHOD, and a maternal no observed adverse
effect level (NOAEL) was established at 13 times the RHOD.
Abortions were observed in pregnant rabbits administered tobramycin via subcutaneous injection at
180 times the RHOD. Tobramycin did not affect fetal development when administered by
subcutaneous injection to pregnant rats at doses 450 times the RHOD.

The background risk of major birth defects and miscarriage for the indicated population is unknown.
However, the background risk in the U.S. general population of major birth defects is 2 to 4%, and
of miscarriage is 15 to 20%, of clinically recognized pregnancies.
Data
Animal Data
Embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral
gavage on gestation days 6 to 18, to target the period of organogenesis. Loteprednol etabonate
produced fetal malformations at doses ≥ 0.1 mg/kg/day (0.54 times the recommended human
ophthalmic dose (RHOD) based on body surface area, assuming 100% absorption of loteprednol
etabonate). Spina bifida (including meningocele) was observed at doses ≥ 0.1 mg/kg/day, and
exencephaly and craniofacial malformations were observed at doses ≥ 0.4 mg/kg/day (2.1 times the
RHOD). At 3 mg/kg/day (16 times the RHOD), loteprednol etabonate was associated with increased
incidences of abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, and
delayed ossification. Abortion and embryofetal lethality (resorption) occurred at doses ≥ 6
mg/kg/day (32 times the RHOD). A NOAEL for developmental toxicity was not established in this
study. The NOAEL for maternal toxicity in rabbits was 3 mg/kg/day.
Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral
gavage on gestation days 6 to 15, to target the period of organogenesis. Loteprednol etabonate
produced fetal malformations, including absent innominate artery at doses ≥ 5 mg/kg/day (13 times
the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body
weight and decreased skeletal ossification at doses ≥ 50 mg/kg/day (135 times the RHOD).
Embryofetal lethality (resorption) was observed at 100 mg/kg/day (270 times the RHOD). The
NOAEL for developmental toxicity in rats was 0.5 mg/kg/day (1.3 times the RHOD). Loteprednol
etabonate was maternally toxic (reduced body weight gain) at doses of ≥ 50 mg/kg/day. The NOAEL
for maternal toxicity was 5 mg/kg/day.
A peri-/postnatal study was conducted in rats administered loteprednol etabonate by oral gavage
from gestation day 15 (start of fetal period) to postnatal day 21 (the end of lactation period). At doses
≥ 0.5 mg/kg/day (1.3 times the RHOD), reduced survival was observed in live-born offspring. Doses
≥ 5 mg/kg/day (13 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract.
Doses ≥ 50 mg/kg/day (135 times the RHOD) produced maternal toxicity (reduced body weight
gain, death), decreased number of live-born offspring, decreased birth weight, and delays in
postnatal development. A developmental NOAEL was not established in this study. The NOAEL
for maternal toxicity was 5 mg/kg/day.

An embryofetal study was conducted in pregnant rabbits administered 20 or 40 mg/kg/day
tobramycin by subcutaneous injection on gestational days 6 to 18, to target the period of
organogenesis. Abortions and maternal toxicity (renal nephrosis and cortical tubular necrosis) were
observed at both dose levels. The developmental and maternal lowest observed adverse effect level
(LOAEL) is 20 mg/kg/day (180 times the RHOD based on body surface area, assuming 100%
absorption of tobramycin). An embryofetal study was conducted in pregnant rats administered 50 or
100 mg/kg/day tobramycin by subcutaneous injection on gestational days 6 to 15, to target the period
of organogenesis. No effects on development, reproduction, or maternal toxicity were reported. The
developmental and maternal NOAEL is 100 mg/kg/day (450 times the RHOD).
Lactation
There are no data on the presence of loteprednol etabonate or tobramycin in human milk, the effects
on the breastfed infant, or the effects on milk production. The developmental and health benefits of
breastfeeding should be considered, along with the mother’s clinical need for Loteprednol Etabonate
and Tobramycin Ophthalmic Suspension and any potential adverse effects on the breastfed infant
from Loteprednol Etabonate and Tobramycin Ophthalmic Suspension.
Pediatric Use
Two trials were conducted to evaluate the safety and efficacy of Loteprednol Etabonate and
Tobramycin Ophthalmic Suspension (loteprednol etabonate and tobramycin ophthalmic suspension)
in pediatric subjects age zero to six years; one was in subjects with lid inflammation and the other
was in subjects with blepharoconjunctivitis.
In the lid inflammation trial, Loteprednol Etabonate and Tobramycin Ophthalmic Suspension with
warm compresses did not demonstrate efficacy compared to vehicle with warm compresses. Patients
received warm compress lid treatment plus Loteprednol Etabonate and Tobramycin Ophthalmic
Suspension or vehicle for 14 days. The majority of patients in both treatment groups showed reduced
lid inflammation.
In the blepharoconjunctivitis trial, Loteprednol Etabonate and Tobramycin Ophthalmic Suspension
did not demonstrate efficacy compared to vehicle, loteprednol etabonate ophthalmic suspension, or
tobramycin ophthalmic solution. There was no difference between treatment groups in mean change
from baseline blepharoconjunctivitis score at Day 15.
There were no differences in safety assessments between the treatment groups in either trial.
Geriatric Use
No overall differences in safety and effectiveness have been observed between elderly and younger
patients.

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.

Adverse reactions have occurred with steroid/anti-infective combination drugs which can be
attributed to the steroid component, the anti-infective component, or the combination.
Loteprednol Etabonate and Tobramycin Ophthalmic Suspension:
In a 42-day safety study comparing Loteprednol Etabonate and Tobramycin Ophthalmic Suspension
to placebo, ocular adverse reactions included injection (approximately 20%) and superficial punctate
keratitis (approximately 15%). Increased intraocular pressure was reported in 10% (Loteprednol
Etabonate and Tobramycin Ophthalmic Suspension) and 4% (placebo) of subjects. Nine percent
(9%) of Loteprednol Etabonate and Tobramycin Ophthalmic Suspension subjects reported burning
and stinging upon instillation.
Ocular reactions reported with an incidence less than 4% include vision disorders, discharge, itching,
lacrimation disorder, photophobia, corneal deposits, ocular discomfort, eyelid disorder, and other
unspecified eye disorders. The incidence of non-ocular reactions reported in approximately 14% of
subjects was headache; all other non-ocular reactions had an incidence of less than 5%.
Loteprednol etabonate ophthalmic suspension 0.2% - 0.5%
Reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be
associated with infrequent 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 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 mm Hg)
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.
Tobramycin ophthalmic solution 0.3%
The most frequent adverse reactions to topical tobramycin are hypersensitivity and localized ocular
toxicity, including lid itching and swelling and conjunctival erythema. These reactions occur in less
than 4% of patients. Similar reactions may occur with the topical use of other aminoglycoside
antibiotics.
Secondary Infection
The development of secondary infection has occurred after use of combinations containing steroids
and antimicrobials. Fungal infections of the cornea are particularly prone to develop coincidentally
with long-term applications of steroids.

The possibility of fungal invasion must be considered in any persistent corneal ulceration where
steroid treatment has been used.
Secondary bacterial ocular infection following suppression of host responses also occurs.
To reports 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--2356-2340.
Toll free phone: 19999
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc
• Other GCC States:
Please contact the relevant competent authority.

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

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.
Loteprednol etabonate is structurally similar to other corticosteroids. However, the number 20
position ketone group is absent. 

The anti-infective component in the combination (tobramycin) is included to provide action against
susceptible organisms. In vitro studies have demonstrated that tobramycin is active against
susceptible strains of the following microorganisms:
Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative),
including penicillin-resistant strains.
Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic 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.

In a controlled clinical study of ocular penetration, the levels of loteprednol etabonate in the aqueous
humor were found to be comparable between Loteprednol Etabonate Ophthalmic Suspension and
Loteprednol Etabonate and Tobramycin Ophthalmic Suspension treatment groups.
Results from a bioavailability study in normal volunteers established that plasma levels of
loteprednol etabonate and Δ1 cortienic 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 ophthalmic suspension 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 0.5% loteprednol
etabonate.

Carcinogenesis
Long-term animal studies have not been conducted to evaluate the carcinogenic potential of
loteprednol etabonate or tobramycin.
Mutagenesis
Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma TK assay,
a chromosome aberration test in human lymphocytes, or in an in vivo mouse micronucleus assay.
Impairment of Fertility
Oral treatment of female and male rats with 25 mg/kg/day of loteprednol etabonate (67 times the
RHOD based on body surface area, assuming 100% absorption) prior to and during mating caused
preimplantation loss and decreased the number of live fetuses/live births. The NOAEL for fertility
in rats was 5 mg/kg/day (13 times the RHOD). Subcutaneous administration of male and female rats with tobramycin did not affect mating behavior or cause impairment of fertility at 100 mg/kg/day
(450 times the RHOD based on body surface area, assuming 100% absorption).

Benzalkonium Chloride, Glycerol, Tyloxapol, Edetate disodium, Povidone K 90, Sodium Hydroxide
1N And / or Sulfuric Acid 5N, Water for injection.

Not applicable.

2 years

Do not store above 30 °C. Do not freeze
Keep out of the reach and sight of children.

Primary Container: LDPE opaque bottle with LDPE nozzle and HDPE cap.
Secondary Container: Carton label and PIL

No special requirements.