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8/8/2019 Lloteflam: Loteprednol etebonate
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Loteprednol etabonate
The designer steroid Specifically tailored for the eyes
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Loteprednol etabonate (LE):The designer steroid
Loteprednol etabonate is a novel, site-
active corticosteroid which is designed toretain the anti-inflammatory efficacy of a
corticosteroid while lowering the risk of typical corticosteroid.
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Site Active (soft drug) Concept
The site active (soft drug) concept wasintroduced in 1980. It was developed byNicholas Bodor and is used to design drugs thatcan be deactivated in the body after their therapeutic effects have been achieved. Thisgreatly reduces the risk of side effects
Ref. : J. of ocular pharmacology 1994 10(1):3-15
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Loteprednol & the Site Active (SoftDrug) concept
Prednisolone relatedcompounds
(inactive)Loteprednol etabonate
(Active form)
Modification
Ester hydrolysis
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Loteprednol alterations in the chemical structure
C 17C 20
Ketone group atC20 is removed
Ester groupadded
Ester group
Higher lipophilicity
Better tissuepenetration
Lesser propensity to
cause cataract
Faster & predictabledrug metabolism toinactive metabolite
Low concentrations
in plasma
Low concentrations
in aqueous humor
No clinically significantHPA axis supression
Lesser Propensity for systemic side effects
Lesser rise in IOP
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Lotiprednol: Pharmacokinetics
High lipophilicity therefore good ocular penetrationDrug absorption highest in the corneaGood concentration in the corneaPlasma levels below the limit of detectionthus minimising systemic side effects
Ref: Biodrugs 1998; 10(4): 329-339Drugs of today 2000; 36(5): 313-320
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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
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Loteprednol: Indications
Giant Papillary conjunctivitis (GPC)
Seasonal Allergic conjunctivitis (SAC)
Vernal Kerato conjunctivitis (VKC)Post-operative Inflammatoryconditions (Post Cataract Surgery)
Inflammatory conditions of the Eye(Uveitis)
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LOTEPREDNOL IN ALLERGIC CONJUNCTIVITIS
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Scoring Systems Used in the Measurement of Allergic Conjunctivitis Signs and Symptoms
Itching0
1
2
3
4
Absent
Trace
Mild
Moderate
Severe
No desire to rub eyelids
Rare desire to rub eyelids
Occasional desire to rubeyelidsFrequent desire to rub eyelidsConstant desire to rub eyelids
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Scoring Systems Used in the Measurement of Allergic Conjunctivitis Signs and Symptoms(contd.)
PapillaeScore Description
0 Normal upper conjunctiva
1 Uniform velvety papillary appearance
2 Nonuniform appearance with papillae covering thesuperior conjunctival surface;
3 Nonuniform appearance with giant papillae
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Scoring Systems Used in the Measurement of Allergic Conjunctivitis Signs and Symptoms(contd.)
Lens intoleranceScore 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
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Scoring Systems Used in the Measurement of Allergic Conjunctivitis Signs and Symptoms (contd.)
Investigator globalassessment and patientglobal assessment0
1
2
3
4
Fully controlled
Reasonablycontrolled
Slight
improvement
Unchanged
Worse
The inflammation is cured,
The inflammation isdiminished,
Small decrease in signs or
symptoms
No response
Overall increase
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Loteprednol: Giant PapillaryConjunctivitis
Aim: To evaluate the safety and efficacy of LE 0.5% in reducing ocular signs and symptomsacompanying Giant Papillary ConjunctivitisNo. of centres : 14No. 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
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Loteprednol: Giant PapillaryConjunctivitis (contd.)Measure Loteprednol
N Mean
PapillaeBaselineDay 35
10996
2.31.2
ItchingBaselineDay 35
10996
2.60.4
Lensintolerance Baseline
Day 3510997
2.20.5
Am. J. of Ophthalmology 1997; 455-464
Biodrugs 1998; 10(4): 329-339
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p < 0 . 0 0 1 p = 0 . 0 0 1 p = 0 . 0 5 3
7 78 7
8 1
9 5
5 1
7 8
1 0 0
8 0
6 0
4 0
2 0
0P a p i l l a e I t c h i n g L e n s
P l a c e b oL E
%
R
espo
nding
Loteprednol: Clinical EfficacyStudies (Contd.)
The proportion of patients at final visit with a decrease in severity of at least 1 grade in papillae, itching, and lens intolerance (Lens)
7 89 5
8 7
02 04 0
6 08 0
1 0 0
Pa p illa e Itch in g L en s
% R e s p o n di
The rapid therapeutic response, combined with low incidenceand transient nature of any increase in intraocular pressure,suggests that loteprednol may provide the clinician with an
appropriate treatment for giant papillary conjunctivitis.
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Loteprednol:Seasonal AllergicConjunctivitisAim: 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 seasonand continuing for 6 weeks
Am J Ophthalmol 1997; 123: 791-797
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9 4
0
2040
60
80
100
1
% Effica
Results:The proportion of patients who never developed moderate or severe signs and symptomsduring the peak pollen season was 94% in theLoteprednol group
Loteprednol: Seasonal AllergicConjunctivitis
Loteprednol etabonate is effective in the prophylaxis of Seasonal allergic conjunctivitis and has an acceptable safetyprofile
Am J Ophthalmol 1997; 123: 791-797
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Loteprednol in post-operative inflammation
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Scoring System used in the measurementof Post-operative inflammation (contd.)
Anterior chamber inflammation (ACI)-Sum of cell and flare score
0 None to trace
1-2 Mild3-4 Moderate (required at baseline)
5-6 Marked
7-8 Severe
9 Hypopyon and severe flare
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Loteprednol: Post-operativeinflammationAim: the safety and efficacy of loteprednol etabonate (LE) 0.5% in
controlling the anterior chamber cell and flare reaction inpatients undergoing cataract surgery with intraocular (IOL)implantation was studied.
Patients : 102 undergoing cataract removal and IOL implantationwho, on the day after surgery exhibited a minimum ACI ratingof 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
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Loteprednol: Post-operativeinflammation (Contd.)Results: The proportion of patients with ACIresolved by the final visit was 56 (55%) of 102 in theLoteprednol group.
Anterior Chamber Inflammation (ACI score)
Loteprednol Etabonate
Baseline 3.5+0.1
Final visit 0.9
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Loteprednol: Post-operativeinflammation (Contd.)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
LE
ConclusionLoteprednol etabonate clinically
significant in the treatment of post-operative inflammation.There was no rebound of signsand symptoms after cessationof therapy. The safety profile of LE was excellent with littleevidence of clinically significantelevations of IOP or deleteriouseffects of postocular surgeries
Ophthalmology 1998; 105: 1780-1786
Proportion of patientswhoseinflammationwas resolved at final visit
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Loteprednol: Anterior uveitis
LE and PA were clinically equivalent in their ability to achievedisease resolution..
Ref.: Pharmazie 2000(5);3:178-183
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Loteprednol etabonate:
Indian Study
Cipla data on file
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Loteprednol: Cipla Data on File
Aim: To evaluate the safety and efficacy of loteprednol etabonate 0.5% incontrolling chamber cell and flare reactions in Indian patients having cataractsurgery with intraocular lens implantationStudy conducted: Ophthalmology dept. of L.V. Prasad Eye InstituteResults: Efficacy
Anterior Chamber Inflammation (ACI)The resolution rate for the evaluable patients was 59.09% at day, 3, 94.2% atday 8 and 97.62% at day 15 which was statistically significant*p
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Loteprednol: Cipla Data on File(Contd.)
The cell scores reducedfrom 2.61+0.10 atbaseline to 0.13+0.07 atday 15 ** p < 0.0001
The flare scores reduced from2.61+0.10 at baseline to0.17+0.08 at day 15
** p < 0.0001
0
0.5
1
1.52
2.5
3
B a s e
l i n e
D a y 3
D a y 8
D a y 1
5
00.5
11.5
22.5
33.5
B a s e
l i n e
D a y 3
D a y 8
D a y 1
5
Cell Scores (n=23) Flare Scores (n=23)
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Loteprednol: Cipla Data on File(Contd.)
0
1
2
3
4
5
6
Baseline Day 3 Day 8 Day 15
Total Scores (n=23)
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Loteprednol: Cipla Data on File(Contd.)
Safety
The study drug was well tolerated. The commonly reported adverse eventswere pain and tearing.
There was no clinically significant change in IOP of the patients under treatment with the 0.5% loteprednol etabonate during the study
BaselineMean+SE
Day 3Mean+SE
Day 8Mean+SE
Day 15Mean+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
BaselineMean+SE
Day 3Mean+SE
Day 8Mean+SE
Day 15Mean+SE
Day 22Mean+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
Thus, Loteprednol etabonate 0.5% suspension is and effective
and well tolerated drug for the treatment of
post-operative inflammation in cataract surgery
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Loteprednol: Safety andTolerabilityIntraocular Pressure Response to loteprednol etabonate inknown steroid respondersAim: To evaluate the comparative potential of topical loteprednoletabonate and prednisolone acetate to raise the IOP in apopulation of individuals known to be steroid responders
n=28Results: The mean IOP for each group at each time period
Mean IOP Elevation
Drug From Baseline
mmHg
Day 42 mmHg p
Loteprednoletabonate
17.4 mmHg 21.5 mmHg p
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Loteprednol:Safety and Tolerability
Conclusion: LE has the anti-inflammatory advantages of prednisolone but without the associated higher risk of significantIOP.
Journal of Ocular Pharmacology; 1993: V 9(3): 157-165
0
5
10
15
20
25
30
0 14 28 42
Intraocu larPre ssure
(mm
Hg)
LE = 4.1 Hg
PA = 9mmHg
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Safety and Tolerability
71.40%
30.80% 30.80%21.40%
7.10%
38.50%
0.00%
10.00%20.00%30.00%40.00%50.00%
60.00%70.00%80.00%
Weakresponders
Moderateresponders
Highresponders
% r i s e i n I O
P
LE
PA
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Loteprednol:Safety and Tolerability
MoleculeParameters
DexamethasoneBetamethasone
Fluorome-thalone
Loteprednol
IOP elevation in generalpopulation percentage
Mean rise of IOP (mmHg)30%4.6-9.08 4.82
3.0%0.93
IOP elevation in steroidresponders percentage
Mean rise of IOP (mmHg)100%23.7
60.5%6.9-8.1
33%4.0
IOP elevation in 257 LE treated patients compared to other steroids
Ref:- Advances in ocular imunology 1994;245-249
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Loteprednol: Indications
Loteprednol etabonate is indicated for thetreatment of
Steroid responsive inflammatory conditionsof anterior segment of the globe such asallergic conjunctivitis, keratitis, iritis, cyclitis,selected infective conjunctivitis.
Giant papillary conjunctivitis
Treatment of post-operative inflammationfollowing ocular surgery
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Loteprednol:Dosage and AdministrationSteroid responsive disease treatment
Apply one or two drops of loteprednol etabonate into theconjunctival sac of the affected eye(s) four times daily.During the initial treatment within the first week, the dosingmay be increased, upto 1 drop every hour, if necessary. Careshould be taken not to discontinue therapy prematurely. If signs and symptoms fail to improve after two days. thepatient should be re-evaluated
Post-operative inflammationApply one or two drops of loteprednol etabonate into theconjunctival sac of the operated eye(s) four times dailybeginning 24 hours after surgery and continuing throughoutthe first 2 weeks of the post-operative period
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Loteprednol: Contraindications/Druginteractions
Hypersensitivity to the steroid
Most viral diseases of the cornea andthe conjunctiva
Drug interactions: not studied
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Loteprednol: Special Population
Pregnancy: Risk to benefit ratio
Nursing mothers: caution to beexercised
Paediatrics: safety and effectivenessnot established
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Loteprednol: Side effects
Side effects observed in 5-15% of thepatients
Abnormal vision/blurring
Burning on instillation
Foreign body sensation
Chemosis
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Loteprednol: Fullfills the characteristic of a novel steroid
It is highly lipophilicAchieves good concentration in oculartissuesIs site-specificHas demonstrated efficacy in a range of ophthalmic conditions that include theexternal tissues (conjunctiva) and theinternal tissue of the anterior segmentHas minimal systemic toxicityIs safe over a reasonable period of time
Ref.: 1) Pharmazie 55(2000):3-178-183
2) Biodrugs 1998 10(4):329-339
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Loteprednol: Fullfills the characteristic of a novel steroid (Contd.)
Loteprednol etabonate has a very lowpropensity to raise intraocular pressure,thus,
Safe for glaucoma patientsSafe for long-term use in allergy and post-operative surgery
Safe for steroid responders (individualssensitive to steroid)Safe for elderly