Fixed-Dose Combination of Tafluprost and Timolol
Fixed-Dose Combination of Tafluprost and Timolol
Fixed-Dose Combination of Tafluprost and Timolol
DOI 10.1007/s12325-014-0151-7
REVIEW
ABSTRACT
prostaglandintimolol
([13 mmHg)
previous
controlled
and
double-masked
clinical trials with DuoTrav (Alcon, Fort
TIM
ocular
in
open-angle
glaucoma
and
and
fixed-combination
beyond.
Compared
to
are discussed.
J. Vuorinen T. Huttunen
Oy 4Pharma Ltd, Turku, Finland
J. Tuominen
Department of Mathematics and Statistics,
University of Turku, Turku, Finland
A. Ropo
Santen Oy, Clinical Research and Medical Affairs,
Helsinki, Finland
N. Pfeiffer
Department of Ophthalmology, Mainz University
Medical Center, Mainz, Germany
INTRODUCTION
A new preservative-free fixed-dose combination
product consisting of 0.0015% tafluprost and
0.5% timolol [TAF/TIM, Santen Oy, Tampere,
Finland; Marketing authorization pending at
time of manuscript preparation. For the other
reviewed products proprietary names Xalacom
933
fluorine
and Ganfort.
prostaglandintimolol
17,18,19,20-tetranor-PGF2a-isopropyl ester) is a
prodrug. The free acid of tafluprost is an FP
daytime
underestimate
the
relative
efficacy
of
combination products). Additional issues
atoms;
this
affects
measurements
both
the
fixed-combination
tended
to
934
timolol
non-responders.
Despite
these
challenges, additional IOP reduction is
METHODS
Thus,
these
figures
represent
fair
irritation.
[27].
Open-label
or
investigator-masked
(single-masked) studies were not included due
In
most
papers,
drug-related
935
Table 1 Different xed-combination prostaglandintimolol drugs in double-blind, controlled, phase III clinical trials based
on the literature (excluding studies using crossover design, run-in drug, or direct switch from previous medication)
Drug
Xalacom
Number of
patients
Endpoint
255
3 months
Dataset
Dosing time of
xed combination
References
ITT
Evening
PP
Morning
164
12 months
Xalacom
129
3 months
ITT
Evening
170
3 months
ITT
Evening
DuoTrav
151
3 months
PP
Morning
155
3 months
PP
Morning
DuoTrav
82
3 months
ITT
Morning
PP
Morning
Xalacom
Xalacom
DuoTrav
168
12 months
DuoTrav
154
6 weeksa
ITT
Morning
372
6 weeks
PP
Morning
Ganfort
178
3 weeks
ITT
Morning
533
3 months
ITT
Morning
Ganfort
533b
12 monthsb
ITT
Morning
3 months
PP
Morning
DuoTrav
DuoTrav
Ganfort
Ganfort
516
TAF/TIM
201
3 months
ITT
Morning
TAF/TIM
283
3 months
ITT
Morning
IOP intraocular pressure, ITT intention-to-treat, PP per-protocol, TAF/TIM xed-dose combination of 0.0015% tauprost
and 0.5% timolol
a
The endpoint calculated as a combined reduction in IOP over all time points during the 12-month or 6-week period
b
Continuation of study by Brandt et al. [18] (same patients)
c
In PP: 256 patients treated with preservative-free Ganfort and 260 patients with preserved Ganfort. By chance same
baseline IOP
RESULTS
Intraocular Pressure
936
Table 2 Incidence of conjunctival/ocular hyperemia and ocular irritation (burning, stinging, itching, foreign body
sensation, pain, pruritus, ocular discomfort, and dry eye sensation) in percentage of patients in safety analyses
Drug
Number of
patients in
safety analysis
Duration of
treatment
Preservative
Xalacom
262
3 months
BAC (0.02%)
Xalacom
200
12 months
Irritation
(%)
References
3.1
2.3
Diestelhorst and
Larsson [39]
BAC (0.02%)
2.5
9.0
129
3 months
BAC (0.02%)
8.5
8.5
Xalacom
170
3 months
BAC (0.02%)
1.8
N/ac
161
3 months
BAC (0.015%)
12.4
11.8
DuoTrav
161
3 months
BAC (0.015%)
14.3
23.6
85
3 months
BAC (0.015%)
14.1
14.1
DuoTrav
207
12 months
BAC (0.015%)
15.0
14.4
157
6 weeks
BAC (0.015%)
10.8
11.5
DuoTrav
193
6 weeks
BAC (0.015%)
13.0
16.6
11.8
12.8
Xalacom
DuoTrav
DuoTrav
DuoTrav
Hyperemia
(%)
195
6 weeks
Polyquad
Ganfort
176
3 weeks
BAC (0.005%)
19.3
18.8
533
3 months
BAC (0.005%)
22.7
20.5
533b
12 months
BAC (0.005%)
25.7
23.8
282
3 months
BAC (0.005%)
19.5
8.5
278
3 months
Preservative free
21.2
14.4
TAF/TIM
201
6 months
Preservative free
8.0
7.0
TAF/TIM
283
6 months
Preservative free
6.4
12.7
Ganfort
Ganfort
Ganfort
If information available in publication, percentages calculated from number of patients with individual adverse events,
otherwise by summing incidences
BAC benzalkonium chloride, IOP intraocular pressure, ITT intention-to-treat, PP per-protocol, TAF/TIM xed-dose
combination of 0.0015% tauprost and 0.5% timolol
a
Polyquad used at 0.001%
b
Continuation of study by Brandt et al. [18] (same patients)
c
Not possible to assess due to incomplete data in publication
937
baseline
IOP
of
29 mmHg.
Naturally,
heterogeneity was increased, when the studies
938
Side Effects
incidence
(Table 2).
tolerability
hyperemia
with
occurred
at
the
highest
occurrence
939
DISCUSSION
940
mean
around
baseline
pressures
of
preservatives.
Xalacom
which
can
be
expected
to
cause
vasoconstriction [7] and thereby counteract
contains
very
high
24].
rather
All
prostaglandin
analogs
are
frequently
ocular
irritation
(924%)
and,
indeed,
941
bimatoprost-free
(17-phenyl-
significant
DuoTrav)
plausible
crossover
18,19,20-trinor-PGF2a)
can
acid
has
also
be
comparison
studies
have
been
CONCLUSION
incidence of side effects among the four fixedcombination products (Table 2). The shortest of
the
trials
has
lasted
only
3 weeks
(with
(Fig. 2).
Hence,
to
avoid
the
942
ACKNOWLEDGMENTS
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943
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944