Loteprednol etabonate

“The designer steroid”

Specifically tailored for the eyes
Loteprednol etabonate (LE):
“The designer steroid”

Loteprednol etabonate is a novel, site-

active corticosteroid which is designed to
retain the anti-inflammatory efficacy of a
corticosteroid while lowering the risk of
typical corticosteroid.
Site Active (soft drug) Concept

The ‘site active’ (soft drug) concept was

introduced in 1980. It was developed by
Nicholas Bodor and is used to design drugs that
can be deactivated in the body after their
therapeutic effects have been achieved. This
greatly reduces the risk of side effects

Ref. : J. of ocular pharmacology 1994 10(1):3-15

Loteprednol & the Site Active (Soft
Drug) concept

Prednisolone related
Modification
compounds Loteprednol etabonate
(inactive) (Active form)

Ester
hydrolysis
 Loteprednol alterations in the chemical structure

C20 C17

Ester group
Ketone group at Ester group
C20 is removed added
Higher lipophilicity
Lesser Faster & predictable
propensity to drug metabolism to Better tissue
cause cataract inactive metabolite penetration

Low concentrations Low concentrations

in plasma in aqueous humor

• No clinically significant
Lesser rise in IOP
HPA axis supression
• Lesser Propensity for
systemic side effects
Lotiprednol: Pharmacokinetics

 High lipophilicity therefore good ocular

penetration
 Drug absorption highest in the cornea
 Good concentration in the cornea
 Plasma levels below the limit of detection
thus minimising systemic side effects

Ref: Biodrugs 1998; 10(4): 329-339

Drugs of today 2000; 36(5): 313-320
Loteprednol is the only topical ophthalmic
corticosteroid which has the broadest
range of indications compared to the
currently available steroids.
Ref.: Drugs Rand D 2002;3(3):154-157
Loteprednol: Indications
 Giant Papillary conjunctivitis (GPC)
 Seasonal Allergic conjunctivitis (SAC)
 Vernal Kerato conjunctivitis (VKC)
 Post-operative Inflammatory
conditions (Post Cataract Surgery)
 Inflammatory conditions of the Eye
(Uveitis)
LOTEPREDNOL IN ALLERGIC
CONJUNCTIVITIS
Scoring Systems Used in the Measurement of
Allergic Conjunctivitis Signs and Symptoms
Itching
0 Absent No desire to rub eyelids

1 Trace Rare desire to rub eyelids

2 Mild Occasional desire to rub

eyelids
3 Moderate Frequent desire to rub eyelids
Constant desire to rub eyelids
4 Severe
Scoring Systems Used in the Measurement of
Allergic Conjunctivitis Signs and Symptoms
(contd.)
Papillae
Score Description
0 Normal upper conjunctiva

1 Uniform “velvety” papillary appearance

2 Nonuniform appearance with papillae covering the

superior conjunctival surface;

3 Nonuniform appearance with giant papillae

Scoring Systems Used in the Measurement of
Allergic Conjunctivitis Signs and Symptoms
(contd.)
Lens intolerance
Score Description

0 Fully controlled; able to comfortably wear lenses

for longer than 6 h

1 Reasonably controlled; able to comfortably wear

lenses longer than 3 h

2 Partially controlled; able to comfortably wear

lenses for longer than 45 min but less than 3 h

3 Uncontrolled: able to comfortably wear lenses for

less than 45 min
Scoring Systems Used in the Measurement of
Allergic Conjunctivitis Signs and Symptoms (contd.)
Investigator global
assessment and patient
global assessment
0
Fully controlled The inflammation is cured,

1
Reasonably The inflammation is
controlled diminished,

2 Slight Small decrease in signs or

improvement symptoms
3
Unchanged No response
4
Worse Overall increase
Loteprednol:Giant Papillary
Conjunctivitis

Aim: To evaluate the safety and efficacy of LE 0.5% in reducing ocular signs and symptoms
acompanying Giant Papillary Conjunctivitis
No. of centres: 14
No. of patients:
n=219 patients (soft contact lens, n = 182, hard contact lens, n = 35). Daily wear was reported by
58% of patients.

Duration: 6 weeks

American Journal of Ophthalmology 1997; 123: 455-464

 Loteprednol:Giant Papillary
Conjunctivitis (contd.)
Measure Loteprednol
N Mean
Papillae
Baseline 109 2.3
Day 35 96 1.2
Itching
Baseline 109 2.6
Day 35 96 0.4
Lens
intolerance
Baseline 109 2.2
Day 35 97 0.5

Am. J. of Ophthalmology 1997; 455-464

Biodrugs 1998; 10(4): 329-339
 Loteprednol: Clinical Efficacy
Studies (Contd.)
The rapid
11 00therapeutic
0 response,
9 5
9p 5= 0 . 0 0 with
combined 1 low
p8 7= incidence
0 . 0 5 3
0 p < 0 . 0 0 1
78 8 7
and transient
88 00 nature
7 8 of any increase 8 1in intraocular pressure,
7 7
suggests6that loteprednol may provide the clinician with an
% R e s p o n d in g

0
46 00 treatment
appropriate 5 for
1 giant papillary conjunctivitis.
24 00
0
2 0
P a p illa e Itch in g Lens
0 % R
P a p i ll a e I t ec s hp oi nn d gin g L e n s
L E P l a c e b o

The proportion of patients at final visit with a decrease in severity of

at least 1 grade in papillae, itching, and lens intolerance (Lens)
Loteprednol:Seasonal Allergic
Conjunctivitis
Aim: To evaluate safety and efficacy of loteprednol
etabonate as a prophylactic treatment of SAC
No of patients: 146 adults with the history of SAC
were treated with Loteprednol four times daily,
beginning before the onset of the allergy season
and continuing for 6 weeks
Am J Ophthalmol 1997; 123: 791-797
 Loteprednol: Seasonal Allergic
Conjunctivitis
94
Loteprednol etabonate
100 is effective in the prophylaxis of
Seasonal allergic
80
conjunctivitis and has an acceptable safety
60
profile
40
20

0 1

% E ffic a c y

Results:The proportion of patients who never

developed moderate or severe signs and symptoms
during the peak pollen season was 94% in the
Loteprednol group
Am J Ophthalmol 1997; 123: 791-797
Loteprednol in post-
operative inflammation
Scoring System used in the measurement
of Post-operative inflammation (contd.)
Anterior chamber
inflammation (ACI)-Sum of
cell and flare score
0 None to trace
1-2 Mild
3-4 Moderate (required at baseline)
5-6 Marked
7-8 Severe
9 Hypopyon and severe flare
Loteprednol: Post-operative
inflammation
Aim: the safety and efficacy of loteprednol etabonate (LE) 0.5% in
controlling the anterior chamber cell and flare reaction in
patients undergoing cataract surgery with intraocular (IOL)
implantation was studied.

Patients: 102 undergoing cataract removal and IOL implantation

who, on the day after surgery exhibited a minimum ACI rating
of 3.
Treatment: All patients received Loteprednol 0.5% four times
daily in the eye that was operated on for up to 14 days after
surgery

Ophthalmology 1998; 105: 1780-1786

 Loteprednol: Post-operative
inflammation (Contd.)
Results: The proportion of patients with ACI
resolved by the final visit was 56 (55%) of 102 in the
Loteprednol group.

Anterior Chamber Loteprednol Etabonate

Inflammation (ACI score)

Baseline 3.5+0.1

Final visit 0.9

 Loteprednol: Post-operative
inflammation (Contd.)
100% Conclusion
Loteprednol etabonate clinically
90%
significant in the treatment of
80% post-operative inflammation.
There was no rebound of signs
70% Proportion of and symptoms after cessation
patients of therapy. The safety profile of
60% whose LE was excellent with little
inflammation evidence of clinically significant
50% was resolved elevations of IOP or deleterious
at final visit effects of postocular surgeries
40%

30% Ophthalmology 1998; 105: 1780-1786

20%

10%

0%
LE
Loteprednol: Anterior uveitis

LE and PA were clinically equivalent in their ability to achieve

disease resolution..
Ref.: Pharmazie 2000(5);3:178-183
Loteprednol etabonate:
Indian Study

Cipla data on file

 Loteprednol: Cipla Data on File
Aim: To evaluate the safety and efficacy of loteprednol etabonate 0.5% in
controlling chamber cell and flare reactions in Indian patients having cataract
surgery with intraocular lens implantation
Study conducted: Ophthalmology dept. of L.V. Prasad Eye Institute
Results: Efficacy
Anterior Chamber Inflammation (ACI)
The resolution rate for the evaluable patients was 59.09% at day, 3, 94.2% at
day 8 and 97.62% at day 15 which was statistically significant
*p<0.005; **p<0.0001

Baseline Day 3 Day 8 Day 15

Mean+SE Mean+SE Mean+SE Mean+SE
Cell Scores 2.61+0.10 1.00+0.09* 0.61+0.13** 0.13+0.07**
Flare Scores 2.61+0.10 1.05+0.07* 0.57+0.12** 0.17+0.08**
Total Scores 5.22+0.20 2.05+0.15 1.17+0.25 0.30+0.14
% Change 59.09** 94.20** 97.62**
 Loteprednol: Cipla Data on File
(Contd.)

Cell Scores (n=23) Flare Scores (n=23)

3 3.5
2.5 3
2 2.5
2
1.5
1.5
1 1
0.5 0.5
0 0
e

e
3

15

15
in

in
ay

ay
ay

ay
ay

ay
el

el
D

D
as

as
D

D
B

The cell scores reduced The flare scores reduced from

from 2.61+0.10 at 2.61+0.10 at baseline to
baseline to 0.13+0.07 at
day 15 ** p < 0.0001
0.17+0.08 at day 15
** p < 0.0001
Loteprednol: Cipla Data on File
(Contd.)

Total Scores (n=23)

6

0
Baseline Day 3 Day 8 Day 15
 Loteprednol: Cipla Data on File
(Contd.)

Safety
Thus,
TheLoteprednol etabonate
study drug was well 0.5%
tolerated. The suspension
commonly is andevents
reported adverse effective
were pain and tearing.
and well tolerated drug for the treatment of
There was no clinically significant change in IOP of the patients under
post-operative inflammation
treatment with the 0.5% loteprednolin cataract
etabonate surgery
during the study

Baseline Day 3 Day 8 Day 15

Mean+SE Mean+SE Mean+SE Mean+SE
IOP 13.43+0.47 13.05+0.49 12.61+0.50 12.96+0.45
% Change 0.71 3.86 1.23

Baseline Day 3 Day 8 Day 15 Day 22

Mean+SE Mean+SE Mean+SE Mean+SE Mean+SE
IOP 15.25+0.53 14.50+0.49 13.75+0.32 13.50+0.33 13.00+0.66
% Change -3.11 -7.82 -11.08 -14.65
Loteprednol: Safety and
Tolerability
Intraocular Pressure Response to loteprednol etabonate in
known steroid responders
Aim: To evaluate the comparative potential of topical loteprednol
etabonate and prednisolone acetate to raise the IOP in a
population of individuals known to be steroid responders
n=28
Results: The mean IOP for each group at each time period
Mean IOP Elevation
Drug From Baseline Day 42 mmHg p
mmHg
Loteprednol 17.4 mmHg 21.5 mmHg p<0.05 *(NS)
etabonate
Prednisolone 18.1 mmHg 27.1 mmHg p<0.05 *(S)
Acetate

NS = Non-significant; S = Significant
Loteprednol:
Safety and Tolerability
30
Intraocular Pressure

25
20
(mmHg)

LE = 4.1 Hg
15
PA = 9mmHg
10
5
0
0 14 28 42
Conclusion: LE has the anti-inflammatory advantages of
prednisolone but without the associated higher risk of significant
IOP.
Journal of Ocular Pharmacology; 1993: V 9(3): 157-165
Safety and Tolerability

80.00% 71.40%
70.00%
60.00%
% rise in IOP

50.00% 38.50%
40.00% 30.80% 30.80%
30.00% 21.40%
20.00%
7.10%
10.00%
0.00%
Weak Moderate H igh LE
res ponders res ponders res ponders PA
Loteprednol:
Safety and Tolerability
Molecule Dexamethasone Fluorome- Loteprednol
Parameters Betamethasone thalone

IOP elevation in general

population percentage 30% 3.0%
Mean rise of IOP (mmHg) 4.6-9.08 4.82 0.93

IOP elevation in steroid

responders percentage 100% 60.5% 33%
Mean rise of IOP (mmHg) 23.7 6.9-8.1 4.0

IOP elevation in 257 LE treated patients compared to other steroids

Ref:- Advances in ocular imunology 1994;245-249

Loteprednol: Indications

Loteprednol etabonate is indicated for the

treatment of
 Steroid responsive inflammatory conditions
of anterior segment of the globe such as
allergic conjunctivitis, keratitis, iritis, cyclitis,
selected infective conjunctivitis.
 Giant papillary conjunctivitis
 Treatment of post-operative inflammation
following ocular surgery
Loteprednol:
Dosage and Administration
Steroid responsive disease treatment
Apply one or two drops of loteprednol etabonate 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, upto 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 or two drops of loteprednol etabonate 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
Loteprednol: Contraindications/Drug
interactions
 Hypersensitivity to the steroid
 Most viral diseases of the cornea and
the conjunctiva
Drug interactions: not studied
Loteprednol: Special Population
 Pregnancy: Risk to benefit ratio
 Nursing mothers: caution to be
exercised
 Paediatrics: safety and effectiveness
not established
Loteprednol: Side effects

Side effects observed in 5-15% of the

patients
 Abnormal vision/blurring
 Burning on instillation
 Foreign body sensation
 Chemosis
Loteprednol: Fullfills the characteristic of
a novel steroid
 It is highly lipophilic
 Achieves good concentration in ocular
tissues
 Is site-specific
 Has demonstrated efficacy in a range of
ophthalmic conditions that include the
external tissues (conjunctiva) and the
internal tissue of the anterior segment
 Has minimal systemic toxicity
 Is safe over a reasonable period of time

Ref.: 1) Pharmazie 55(2000):3-178-183

2) Biodrugs 1998 10(4):329-339
Loteprednol: Fullfills the characteristic of
a novel steroid (Contd.)

 Loteprednol etabonate has a very low

propensity to raise intraocular pressure,
thus,
 Safe for glaucoma patients
 Safe for long-term use in allergy and post-
operative surgery
 Safe for steroid responders (individuals
sensitive to steroid)
 Safe for elderly