LATIM

1
LATIM

• LATANOPROST 0.005 TIMOLOL 0.5
• FIXED DOSE
• COMBINATION
• One drop Drops IOP Better

2
Glaucoma Management

• Medication
• Monotherapy.
• Replacement/ Adjunctive therapy
• Fixed Dose Combination 
• Laser treatment
• Surgery

3
LATIM- Partnering Two drugs in a single bottle

• Complimentary mechanism of action of two drugs.
• Good Safety profile
• Unaltered Pharmacokinetics when combined
• Compliance
• Persistency of individual medications
• Reduced time commitment for drop instillation
• Elimination of wash out effect

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Latanoprost Outflow Facilitator

• Latanoprost, is highly specific for and has high
  affinity for the FP subtype prostanoid receptor
• Latanoprost is a prodrug of latanoprost acid
• Latanoprost is hydrolyzed to its active form in
  cornea or in plasma
• Reduction in IOP occurs within 3-4 hours, peaks
  within 8-12 hours and persists for up to 24 hours
  or longer after topical application
• Ref 1. Drugs Ageing 2003 20(8) 597-630
• 2. AHFS Drug Information 2000 2586-2600

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Timolol Beta Blocker

• Timolol, the first ?-blocker to be approved for
  glaucoma in 1974
• Widely used as first-line therapy
• Benchmark against which other ?-blockers and
  second line glaucoma therapies are assessed for
  efficacy and tolerability
• Ref Drugs and Aging 2000 17(6) 477-496

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Latim Latanoprost TimololFixed Combination

• Synergistic Pharmacokinetics
• Dual Benefit
• Pronounced IOP Reduction
• High Compliance

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LTFC Synergy

• A combination therapy of latanoprost and timolol
  has a scientific bearing as the two drugs have
  complementary mechanism of action

Outcome achieved by the fixed combination of
latanoprost and timolol Result of individual
medication The influence each drug exerts
over the other drug
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LTFC Synergy

• Study Demonstration of synergy
• Study designed to evaluate the ocular
  pharmacokinetics of LTFC in cataract surgery
  patients.
• The T max, concentration Cmax and the Area under
  curve (AUC) of timolol and acid of latanoprost
  were determined and compared.
• Journal of Ocular Pharmacology and Therapeutics,
  2002, Vol 18, No.2 127-131

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PharmacokineticsComparison post single dose
(30µl) of LTFC
Based on values from 2-12 hr for acid of
latanoprost and 2-24 hr for timolol.
10
100
Fixed combination
Latanoprost
10
Aqueous Humor concentration (ng/ml)
Aqueous humor conc (ng/ml)
1
0
5
10
15
Time (h)
Latanoprost Aqueous Humor Concentration as
monotherapy and LTFC
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LTFCSynergy

• Method of action compatible pharmacokinetics
  ?effective reduction in IOP.
• Thus , Timolol by its action not only lowers IOP
  but also increases the concentration of
  latanoprost acid .
• Journal of Ocular Pharmacology and Therapeutics,
  2002, Vol 18, No.2 127-131

Latanoprosttimolol fixed dose combination shows
synergistic mechanism of action effectively
lowering IOP than the individual drugs dosed
separately.
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LTFC Efficacy Post Single Dose

• Effect of a single dose administration of fixed
  combination of latanoprost 0.005 and timolol
  0.5 was evaluated.
• A randomized double masked placebo controlled
  study.
• 20 patients with ocular hypertension- LTFC
• 10 patients Placebo

Ref Acta Opth Scand 200179125-128
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LTFC Efficacy Post Single Dose

• Results
• No difference in IOP between baseline and
  placebo.
• IOP reduction LTFC

49 IOP reduction Post Single dose
Ref Acta Opth Scand 200179125-128
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Baseline Placebo Latanoprost Timolol
Diurnal IOP Control
15

• Conclusions
• LTFC statistically significantly reduced IOP
  after single dose administration .
• Maximal reduction after 6.4 hours , which was
  significantly pronounced reduction even after
  48 hours

IOP reduction 24, 48 hours post dose of LTFC
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Study Observations

• The IOP pattern corresponds well to pattern of
  each drug,
• Effect of timolol setting in first lowering IOP
  within 30 minutes , thereafter the effect of
  latanoprost setting in to give a rather longer
  and stable reduction of IOP.
• Decrease of 12.4mmHg corresponded to 49
  reduction compared to the baseline IOP.

Since , The IOP reduction was still pronounced
after 24 hours , a once daily application would
be sufficient . NO EXTRA DROP OF TIMOLOL IS
REQUIRED Fixed combination administered once
daily may increase compliance and there by the
efficacy of the medications also.
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Study 1Comparison of LTFC with its Individual
Components( Morning)

• To evaluate IOP reducing effect of LTFC with its
  individual components
• Methods
• No. Of participants 436
• Study design Randomized double masked
  controlled
• Duration 6 month followed by 6-month open label
  phase
• Patient Profile Glaucoma
• OHT gt 22 mmHg
  if on medication
• gt 30 mm Hg if
  untreated.
• Ref Graefes Arch Clin Exp Ophthalmol
  2002240893-899

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Study 1 Results

• No drift in IOP over a period of 12 months

• Ref Graefes Arch Clin Exp Ophthalmol
  2002240893-899

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28
Fixed combination (n140)
Latanoprost (n147)
26
TImolol (n149)
)
g
H
m
m
24
(

P
O

• The study demonstrated that LTFC applied once
  daily lowered
• IOP more effectively than monotherapy with
  timolol twice daily
• or latanoprost once daily
• Ref Graefes Arch Clin Exp Ophthalmol
  2002240893-899

I

l
a
n
22
r
u
i
D

n
a
e
20
M
18
-4
0
2
13
26
Prestudy
Treatment Time (weeks)
Changes in mean diurnal IOP levels during the
double masked study Week 13 and 26
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Is evening administration more efficacious ???

• The initial clinical trials were based on morning
  administration.
• BUT
• Its a well established fact that latanoprost
  exhibits superior efficacy when administered in
  the evening /night , so when its combined with a
  beta blocker , it seems logical to administer it
  in the evening too.

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24 hrs Efficacy and Safety of LTFC Vs Latanoprost
in POAG patients

• Methods
• No of participants 37
• Patient Profile POAG patients
• Duration
• 6 weeks of medicine free period
• 8 weeks of randomization to LTFC or latanoprost
• dosed once daily in the evening
• Patients were switched to other therapy for 8
  weeks
•  
• Arch Ophthalmol 2005 123 898-902

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Results

• LTFC lowered IOP by 7.5 mmHg
• Latanoprost alone lowered IOP by 4.7 mmHg

LTFC provided a lower absolute IOP , and a
greater reduction from the untreated baseline.

• Arch Ophthalmol 2005 123 898-902

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Timolol
Latanoprost
Fixed combination
27
25
g
23
H

m

• Conclusion
• LTFC improved IOP reduction over 24 hour in
  patients with POAG
• Better efficacy for LTFC than the 1.1-1.2mm Hg as
  compared to clinical trials .

21
m

,
P
O
19
I
17
15
6
10
2
6
11
2
Diurnal
AM
AM
PM
M
P
M
P
AM
Time Points

• COMPARISON DIURNAL IOP CONTROL

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Efficacy Studies Overview
Thus , from the all the efficacy studies , it can
be said that LATIM can be administered once daily
either in the morning or in the evening .
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LATIM Indications

• Latanoprost and timolol maleate fixed combination
  is indicated for reduction of IOP in patients
  with open angle glaucoma or ocular hypertension ,
  who are insufficiently responsive to
  beta-blockers, prostaglandins, or other IOP
  lowering agents , or when the use of combination
  is considered appropriate.

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Dosage and Administration

• One drop of Latanoprost Timolol Fixed
  Combination in the affected eyes once daily .

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LTFC Highlights

• 49 reduction in IOP post single dose.
• 13-36 additional IOP reductions with LTFC as
  compared to those with monotherapy.
• Efficacy maintained over a period of 12 months.
• Safe and well tolerated.
• Improved diurnal IOP control.
• Latanoprost timolol fixed combination is more
  effective at day end diurnal curve than unfixed
  brimonidine 0.2 and timolol 0.5

• A medication which provides consistently low IOP
• Minimizes fluctuations
• Reduces the risk of glaucoma progression
• Added advantage of Once Daily dosing
• Will definitely increase compliance and thereby
  increase the therapeutic efficacy