Bimatoprost with timolol maleate, eye drops, 0.3 mg - 5 mg (base) per mL (0.03%-0.5%), 3 mL, Ganfort® , March 2009
Public summary document for Bimatoprost with timolol maleate, eye drops, 0.3 mg - 5 mg (base) per mL (0.03%-0.5%), 3 mL, Ganfort® , March 2009
Page last updated: 03 July 2009
Public Summary Document
Product: Bimatoprost with timolol maleate, eye
drops, 0.3 mg - 5 mg (base) per mL (0.03%-0.5%), 3 mL,
Ganfort®
Sponsor: Allergan Australia Pty Ltd
Date of PBAC Consideration: March 2009
1. Purpose of Application
The submission sought a restricted benefit listing for the
reduction of elevated intraocular pressure in certain patients with
open-angle glaucoma or ocular hypertension.
2. Background
This combination eye drop had not previously been considered by the
PBAC.
3. Registration Status
Ganfort was registered by the TGA on 15 May 2009 for reduction of
elevated intraocular pressure in certain patients with open-angle
glaucoma or ocular hypertension.
4. Listing Requested and PBAC’s View
Restricted Benefit
Reduction of elevated intra-ocular pressure in patients with
open-angle glaucoma who are not adequately controlled with timolol
maleate 5 mg (base) per mL (0.5%) eye drops or latanoprost eye
drops or bimatoprost eye drops.
Reduction of elevated intra-ocular pressure in patients with ocular
hypertension who are not adequately controlled with timolol maleate
5 mg (base) per mL (0.5%) eye drops or latanoprost eye drops or
bimatoprost eye drops.
For PBAC’s view, see Recommendation and
Reasons
5. Clinical Place for the Proposed Therapy
This fixed combination product provides a therapeutic alternative
to two mono-therapies of the respective components. Administration
of a single product avoids the problem of ‘wash out’
where the first administered drug is physically ‘washed
out’ of the eye by the second drug.
6. Comparator
The submission appropriately nominated the individual components
bimatoprost 0.03% and timolol maleate 0.5%, given concomitantly as
the main comparator
The submission also nominated two secondary comparators:
(1) Latanoprost with timolol maleate.
(2) Bimatoprost and timolol maleate each given as
monotherapy.
7. Clinical Trials
The submission presented one randomised double-blinded
non-inferiority trial (Study 026T) as key evidence in patients with
glaucoma or ocular hypertension in which bimatoprost with timolol
maleate, administered once daily in the morning, was
compared:
(i) with concomitant use of bimatoprost once daily in the evening
and timolol maleate twice daily; and
(ii) with bimatoprost alone once daily in the evening.
As supplementary evidence, the submission presented:
(i) one randomised, evaluator (outcome assessor)-blinded trial
(Martinez 2007) in patients with glaucoma receiving either
bimatoprost with timolol maleate administered once daily in the
evening or a once daily evening dose of latanoprost and timolol
(Xalacom®); and
(ii) three randomised double-blinded trials (Studies 018T, 021T,
and 504T) in patients with glaucoma or ocular hypertension
receiving bimatoprost with timolol or its individual components
(bimatoprost and timolol maleate) given as monotherapy
The key trials published at the time of submission are shown below:
| Trial ID/First Author | Protocol title/Publication title | Publication citation |
| Key trial (comparing Ganfort with concomitant use of the individual components) | ||
| Study 026T | ||
| Hommer A | A double-masked, randomized, parallel comparison of a fixed combination of bimatoprost 0.03%/timolol 0.5% with non-fixed combination use in patients with glaucoma or ocular hypertension. | European Journal of Ophthalmology 2007; vol 17 no.1:53-62 |
| Hommer A, Wickstrøm J, Friis M M, et al | A cost-effectiveness analysis of fixed-combination therapies in patients with open-angle glaucoma: a European perspective. | Current Medical Research and Opinion 2008; vol. 24, No. 4, 1057–1063. |
| Katz LJ, Lewis RA, Batoosingh AL, Liu C; for the Ganfort® Investigators’ Group II. | Bimatoprost/Timolol Fixed Combination: A one-year, double-masked, randomized parallel comparison to its individual components in patients with glaucoma or ocular hypertension. | Poster presentation ARVO, Fort Lauderdale, May2007 |
| Supplementary trial (comparing Ganfort with Xalacom) | ||
| Martinez, A and Sanchez M, 2007 | A comparison of the safety and intraocular pressure lowering of bimatoprost/timolol fixed combination versus latanoprost/timolol fixed combination in patients with open-angle glaucoma. | Current Medical Research and Opinion 2007; 23(5): 1025-1032. |
| Supplementary trials (comparing Ganfort with the individual components given as monotherapy) | ||
| Study 021T | ||
| Brandt JD, Cantor LB, Batoosingh AL, et al ; for the Ganfort® Investigators’ Group | A 3-month, randomized study comparing bimatoprost/timolol fixed-combination therapy to monotherapy with bimatoprost or timolol in patients with glaucoma or ocular hypertension. | Poster presentation IGS, Athens, April 2007 |
| Brandt J.D., Cantor L.B., Katz L.J., et al | Bimatoprost/timolol fixed combination: A 3-month double-masked, randomized parallel comparison to its individual components in patients with glaucoma or ocular hypertension. | Journal of Glaucoma 2008 17(3): 211-216 |
8. Results of Trials
In the key trial (Study 026T), the primary endpoint was mean
intraocular pressure (IOP) at each time point (Hours 0, 2, and 8)
at day 0 and week 3 in the treatment naïve population.
The results of the key trial are summarised below:
Mean IOP (mm Hg) at each scheduled time point in Study
026T: ITT
| Time Point | Ganfort N=178 | Concomitant use of bimatoprost and timolol N=177 | Ganfort vs Concomitant | |
| P-value Difference (95% CI) | ||||
| Base- Line | Hr 0 | 26.2 | 26.4 | 0.410 -0.18 (-0.62,0.25) |
| Hr 2 | 24.9 | 25.2 | 0.300 -0.29 (-0.83,0.26) | |
| Hr 8 | 23.7 | 23.9 | 0.400 -0.26 (-0.85,0.34) | |
| Week 3 | Hr 0 | 16.5 | 15.8 | 0.084 0.60 (-0.08,1.28) |
| Hr 2 | 16.2 | 15.5 | 0.077 0.61 (-0.07,1.29) | |
| Hr 8 | 15.4 | 15.5 | 0.663 -0.15 (-0.80, 0.51) | |
ITT: Intention to treat (Note: the per-protocol results were
consistent with the ITT results),
Hr: Hour, CI: Confidence interval.
The table shows that at week 3, there was no statistically
significant difference in mean IOP values between the Ganfort and
concomitant arms at all time points. The pre-specified
non-inferiority criteria in Study 026T stated that to demonstrate
non-inferiority, the upper limit of the 95% confidence interval for
the difference in mean IOP (fixed minus non fixed) was required to
be less than 1.5mmHg for all 3 time points and less than 1.0mmHg
for at least 2 time points at week 3.
In the supplementary trial (Martinez 2007), the key endpoint was
mean IOP reduction at three time points from baseline to week 4,
and the difference in mean diurnal IOP reduction from baseline to
week 4. The results of Martinez 2007 are summarised below.
IOP reduction (mmHg) at week 4, unadjusted mean (SD) in
Martinez 2007
| Xalacom | Ganfort | Difference (P value) | |
| Week 4 9.00am 12.00noon 3.00pm | 2.2 (0.7) 2.6 (0.8) 1.8 (1.1) | 3.2 (0.7) 3.0 (1.2) 2.2 (1.4) | 1.0 (0.0002) 0.4 (0.1983) 0.4 (0.2844) |
| Diurnal | 2.1 (0.6) | 2.8 (0.9) | 0.7 (0.0214) |
SD = standard deviation, IOP : intraocular pressure
According to the above table, the unadjusted results illustrate
that Ganfort has a superior effect at only one time point (9.00am),
and on diurnal IOP over Xalacom.
The results of Study 026T suggested that overall the safety profile
of Ganfort showed no notable difference to that of concomitant use
of the individual components. The most frequently reported adverse
event was conjunctival hyperaemia, reported less in the Ganfort arm
(19.3%) compared to the concomitant arm (25.6%). The results of
Martinez 2007 suggest that the frequency of most side effects
reported was numerically higher in the Ganfort arm compared to the
Xalacom arm. In particular, 44% of patients in the Ganfort arm
experienced conjunctival hyperaemia compared to 22% in the Xalacom
arm.
9. Clinical Claim
Based on the results of Study 026T, the submission claimed that
bimatoprost with timolol (with single dosing of timolol) was
non-inferior in terms of comparative effectiveness and comparable
in terms of safety over concomitant use of the individual
components (including two doses of timolol). The PBAC supported
this claim.
The submission claimed that according to Martinez 2007, bimatoprost
with timolol was superior in terms of comparative effectiveness
over latanoprost with timolol. As there are small differences in
IOP values between treatment groups at the scheduled time points,
the submission claimed that bimatoprost with timolol was considered
non-inferior in terms of comparative effectiveness over latanoprost
with timolol.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. According to
Study 026T, the equi-effective doses were estimated as bimatoprost
with timolol one drop instilled once daily and concomitant
bimatoprost 0.3mg/mL one drop instilled once daily plus timolol
maleate 5mg/mL one drop instilled twice daily.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year were estimated in the
submission to be between 10,000 – 50,000 in Year 5.
The submission argued that because the patients who received
bimatoprost with timolol would have been treated with two
prostaglandin analogue fixed combinations currently listed on the
PBS (latanoprost with timolol and travoprost with timolol), there
would be no net increase in cost to the PBS/RPBS should bimatoprost
with timolol be listed.
12. Recommendation and Reasons
The PBAC recommended the listing of bimatoprost with timolol
maleate on the PBS and also for inclusion in the Optometrical
Schedule, in accordance with the combination guidelines, on a
cost-minimisation basis compared with its constituent components,
bimatoprost 0.03% and timolol maleate 0.5% eye drops given
concomitantly.
The PBAC agreed that the comparison presented in the submission
supported the claim of non-inferiority of bimatoprost with timolol
maleate with the concomitant use of the individual components based
on an acceptance that the difference in mean intra-ocular pressure
(IOP) is less than than 1.5 mmHg.
The PBAC considered that while the pre-specified non-inferiority
criteria were not met after adjustment for central corneal
thickness, such adjustments have not been a consideration in
previous PBAC recommendations for listing other eye drop products
and therefore were not considered for this submission. The PBAC has
also previously considered the diurnal variation in IOP reduction
with different eye drop products but again considered that this
issue was not pivotal to the consideration for PBS
subsidisation.
The PBAC agreed with the sponsor and recommended changing the
wording of the restrictions for all PBS-listed timolol with
prostaglandin/prostamide analogue combinations so that patients who
are on a timolol/prostaglandin or prostamide analogue combination
do not have to return to monotherapy with timolol prior to a change
in the combination eye drop.
Recommendation
BIMATOPROST with TIMOLOL MALEATE, eye drops, 0.3 mg - 5 mg (base)
per mL (0.03%-0.5%), 3 mL
Restriction:
Restricted Benefit
Reduction of elevated intra-ocular pressure in patients with
open-angle glaucoma who are not adequately controlled with timolol
maleate 5 mg (base) per mL (0.5%) eye drops or prostaglandin or
prostamide analogue monotherapies.
Reduction of elevated intra-ocular pressure in patients with ocular
hypertension who are not adequately controlled with timolol maleate
5 mg (base) per mL (0.5%) eye drops or prostaglandin or prostamide
analogue monotherapies.Max. Qty: 1
Repeats: 5
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
Allergan Australia welcomes this decision by the PBAC to provide
access to a new treatment option for Australian's with ocular
hypertension and open angle glaucoma.
