lloteflam: loteprednol etebonate

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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0

1

2

3

4

5

6

Baseline Day 3 Day 8 Day 15

Total Scores (n=23)


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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

lloteflam: loteprednol etebonate

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