Brinzolamide with timolol maleate, eye drops, 10 mg -5 mg (base) per mL, (1%-0.5%), Azarga® - March 2010
Public Summary Document for Brinzolamide with timolol maleate, eye drops, 10 mg -5 mg (base) per mL, (1%-0.5%), Azarga® - March 2010
Page last updated: 02 July 2010
Public Summary Document
Product: Brinzolamide with timolol maleate,
eye drops, 10 mg -5 mg (base) per mL, (1%-0.5%),
Azarga®
Sponsor: Alcon Laboratories (Australia) Pty
Ltd.
Date of PBAC Consideration: March 2010 PBAC
1. Purpose of Application
To request a Restricted Benefit listing, in both the General and
the Optometrical Schedules, for the reduction of elevated
intraocular pressure in certain patients with open-angle glaucoma
or with ocular hypertension.
2. Background
This combination eye drop had not previously been considered by the
PBAC. A similar product, dorzolamide hydrochloride with timolol
maleate eye drops (Cosopt®), was recommended for
listing at the September 2001 PBAC meeting on a cost-minimisation
basis compared with the individual components.
3. Registration Status
TGA registration for Azarga eye drops occurred on 23 December 2009
for the following indication: Decrease of intraocular pressure
(IOP) in patients with open-angle glaucoma or ocular hypertension
for whom monotherapy with either component provides insufficient
IOP reduction.
4. Listing Requested and PBAC’s View
Restricted Benefit (General and
Optometrical)
Reduction of elevated intro-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;
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.
For PBAC’s view see Recommendation and Reasons
5. Clinical Place for the Proposed Therapy
For a patient in whom the first-line therapy is not sufficiently
effective, a second topical medication can be added. This fixed
combination product provides a therapeutic alternative to two
mono-therapies of the respective components. The sponsor claims it
has the advantage of improving compliance, less ocular toxicity
from preservatives and avoids ‘wash out’ effect of
concomitant treatment if the second drop is administered less than
5 minutes after the first.
6. Comparator
As recommended for a combination product, more than one comparison
was presented.
The submission nominated (1) the individual components given
concomitantly (brinzolamide and timolol) and (2) the combination
product that most prescribers would replace in practice –
dorzolamide/timolol (Cosopt). The PBAC considered the comparators
nominated in the submission were reasonable, however the submission
had not presented any evidence comparing Azarga to its components
given concomitantly.
7. Clinical Trials
The submission presented three randomised trials of the fixed combination of brinzolamide 1% and timolol 0.5% in populations with increased intraocular pressure at baseline;
- one three arm trial, versus (vs) brinzolamide 1% vs timolol 0.5% as monotherapies (Trial C-05-24)
- one trial vs timolol 0.5% monotherapy (Trial C-97-22: a 14 day exploratory study)
- one trial vs dorzolamide 2% and timolol 0.5% in fixed dose combination (Trial C-05-10: a non-inferiority trial)
The submission also presented two trials of brinzolamide 1% and
timolol 0.5% given concomitantly vs dorzolamide 2% and timolol 0.5%
given concomitantly (Michaud 2001, which was a non-inferiority
trial, and Martinez 2009), and two studies of self assessed patient
comfort of Azarga vs Cosopt (Study C-05-49, Mundorf 2008). As
noted, the submission did not present a comparison of the fixed
combination of brinzolamide 1% and timolol 0.5% against its
components taken concomitantly.
The trials published at the time of the submission are as
follows:
| Trial ID / First author | Protocol title / Publication title | Publication citation |
|---|---|---|
| Azarga vs monotherapy | ||
| Azarga vs Cosopt (dorzolamide + timolol) | ||
| Supplementary evidence | ||
| Timolol + brinzolamide or dorzolamide | ||
| Trial C-05-24 | ||
| Kaback, Scoper,
Arzeno, et al Croxtall and Scott |
Intraocular
Pressure-Lowering Efficacy of Brinzolamide 1%/Timolol 0.5% Fixed
Combination Compared with Brinzolamide 1% and Timolol
0.5%. Brinzolamide/timolol: in open-angle glaucoma and ocular hypertension. |
Ophthalmology 2008;
115(10): 1728-1734.e2. Drugs & Aging 2009; 26(5): 437-46 |
| Trial C-05-10 | ||
| Manni et al | The safety and efficacy of brinzolamide 1%/timolol 0.5% fixed combination versus dorzolamide 2%/timolol 0.5% in patients with open-angle glaucoma or ocular hypertension. | J Glaucoma 2009; 18(4): 293-300 |
| Michaud 2001 | Michaud J-E and Friren B. Comparison of topical brinzolamide 1% and dorzolamide 2% eye drops given twice daily in addition to timolol 0.5% in patients with primary open-angle glaucoma or ocular hypertension. | American Journal of Ophthalmology 2001; 132(2): 235-243. |
| Martinez 2009 | A comparison of the long-term effects of dorzolamide 2% and brinzolamide 1%, each added to timolol 0.5%, on retrobulbar hemodynamics and intraocular pressure in open-angle glaucoma patients. | J Ocul Pharmacol Ther 2009; 25(3): 239-48. |
| Self assessed ocular discomfort | ||
| Study C-05-49 | ||
| Vold, Evans, Stewart, et
al. Mundorf 2008 |
A one-week comfort study of
BID-dosed brinzolamide 1%/timolol 0.5% ophthalmic suspension fixed
combination compared to BID-dosed dorzolamide 2%/timolol 0.5%
ophthalmic solution in patients with open-angle glaucoma or ocular
hypertension. A patient preference comparison of Azarga (brinzolamide/timolol fixed combination) vs Cosopt (dorzolamide/timolol fixed combination) in patients with open-angle glaucoma or ocular hypertension. |
Journal of Ocular Pharmacology
and Therapeutics 2008; 24(6): 601-5. Clin Ophthalmol 2008; 2(3): 623-8 |
8. Results of Trials
There were statistically significantly larger reductions in mean
intraocular pressure in patients treated with fixed combination
brinzolamide 1% and timolol 0.5% (Azarga) at 6 months compared with
brinzolamide 1% or timolol 0.5% monotherapies.
None of the differences in mean IOP between the fixed combination
brinzolamide 1% and timolol 0.5% (Azarga) and the fixed combination
dorzolamide 2% plus timolol 0.5% (Cosopt) were statistically
significant, and at 6 and 12 months the upper bound of the 95%
confidence interval (CI) for the mean difference in intraocular
pressure was less than the non-inferiority margin of +1.5mmHg,
therefore Azarga was demonstrated to be non-inferior to Cosopt.
Analysis using the intention to treat population also demonstrated
non-inferiority. The participants of both Trials C-05-24 and C-05-10 were not using
any
intraocular pressure lowering eye-drops at baseline, and therefore
were not the population for whom listing was sought (i.e. elevated
intraocular pressure not adequately controlled with timolol
0.5%).
In the comparison of concomitant dosing of brinzolamide 1% and
timolol 0.5% vs. concomitant dosing of dorzolamide 2% and timolol
0.5% the upper 95% confidence limits to all time points were below
+1.5mmHg, thus non-inferiority of brinzolamide compared with
dorzolamide when used concomitantly with timolol 0.5% up to 3
months was demonstrated. However, this trial did not use the fixed
dose combination, Azarga.
Martinez 2009 reported statistically significant decreases in
resistance index from baseline in patients treated with dorzolamide
in all retrobulbar arteries over 5 years, indicating an improvement
in blood flow, thus reduced probability of visual field defect
progression. No decrease in resistance index was found in patients
treated with brinzolamide.
In Study C-05-49, after two weeks patient assessed discomfort on a
0 to 4 scale was statistically significantly lower in the Azarga
group compared with the Cosopt group, the difference -0.77 (95%CI
-0.36, -1.17), p = 0.0003. In Mundorf 2008, 84/127 patients (66.1%)
expressed a preference for Azarga over Cosopt. These results
indicate that patients generally found Azarga more comfortable to
use than Cosopt. The adverse event profile of Azarga is comparable
to that of brinzolamide 1% and timolol 0.5% given concomitantly,
and is similar to Cosopt, except that Azarga produces less burning,
stinging, and eye pain, though causes more blurred vision.
For PBAC’s view see Recommendation and Reasons
9. Clinical Claim
The submission described Azarga as superior in terms of comparative
effectiveness in lowering intraocular pressure compared with
brinzolamide 1% or timolol 0.5% given as monotherapies, but with
greater toxicity. This description is reasonable. The submission
also described Azarga as “as effective” as Cosopt in
reduction of intraocular pressure and as superior in terms of
comparative safety.
Although the submission did not present a comparison of the fixed
combination of brinzolamide 1 % and timolol 0.5 % against its
components taken concomitantly, the PBAC agreed that it is
reasonable to describe Azarga as superior in terms of comparative
effectiveness in lowering intraocular pressure compared with
brinzolamide 1 % or timolol 0.5 % given as monotherapies, but with
greater toxicity. The PBAC further agreed that the comparison of
the fixed combination Azarga versus the fixed combination Cosopt
presented in the submission supported the claim of non-inferiority
of Azarga with Cosopt.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses are estimated as one drop of Azarga is
equi-effective to one drop of brinzolamide 1% plus one drop of
timolol 0.5%. The submission did not present any evidence to
support the assumption that Azarga is equi-effective compared to
concomitant treatment with its components. One drop of Azarga is
also equi-effective to one drop of Cosopt.
For PBAC’s view see Recommendation and Reasons
11. Estimated PBS Usage and Financial Implications
The likely number of prescriptions dispensed per year was estimated
to be between 50,000 and 100,000 in Year 3. The financial cost per
year to the PBS was < $10 million in Year 3. The
submission’s estimate is reasonable if the market share
estimates are accurate.
12. Recommendation and Reasons
The PBAC recommended the listing of brinzolamide with timolol eye
drops in the General and Optometrical Schedules as a restricted
benefit for elevated intraocular pressure due to open angle
glaucoma/ocular hypertension in a patient in whom this condition is
not adequately controlled with monotherapy. Listing was recommended
on a cost-minimisation basis against the individual components
given concurrently and against the combination product dorzolamide
2 % (base) with timolol 0.5 % (base) eye drops (Cosopt). The
equi-effective doses for the purposes of cost-minimisation are one
drop of the combination brinzolamide with timolol eye drops is
equi-effective to one drop of brinzolamide 1 % eye drops plus one
drop of timolol 0.5 % eye drops; and that one drop of the
combination brinzolamide with timolol eye drops (Azarga) is
equi-effective to one drop of the combination dorzolamide with
timolol eye drops (Cosopt).
Although the submission did not present a comparison of the fixed
combination of brinzolamide 1 % and timolol 0.5 % against its
components taken concomitantly, the PBAC agreed with ESC that it is
reasonable to describe Azarga as superior in terms of comparative
effectiveness in lowering intraocular pressure compared with
brinzolamide 1 % or timolol 0.5 % given as monotherapies, but with greater toxicity.
The PBAC further agreed with the ESC that the comparison of the
fixed combination Azarga versus the fixed combination Cosopt
presented in the submission supported the claim of non-inferiority
of Azarga with Cosopt. In the per protocol analysis, none of the
differences in mean IOP between Azarga and Cosopt were
statistically significant, and at 6 and 12 months the upper bound
of the 95 % CI for the mean difference in intraocular pressure was
less than the non-inferiority margin of +1.5 mmHg, which the PBAC
has previously accepted as the appropriate non-inferiority
margin.
The Committee also accepted the sponsor’s arguments that the
results of the Martinez 2009 study which appear to show an
advantage for dorzolamide over brinozolamide in terms of
progression of visual field deterioration should be discounted as
the very large differential drop out rates in this study make the
results difficult to interpret. Thus overall the PBAC considered it
was reasonable to conclude that non-inferiority had been
demonstrated against the individual components given concurrently
and against the combination product dorzolamide with timolol eye
drops (Cosopt).
The PBAC noted that the dispensed price for maximum quantity (DPMQ)
requested in the submission is based on the current PBS prices of
the individual component brinzolamide and timolol eye drops, which
at $ 29.65 is higher than the current DPMQ of $ 27.49 for the
combination dorzolamide with timolol eye drops. The PBAC requested
this matter be referred to the Pharmaceutical Benefits Pricing
Authority with the advice that the PBAC could see no justification
for the higher price for brinzolamide with timolol eye drops
compared to dorzolamide with timolol eye drops.
The PBAC also recommended a restriction wording of
“elevated intra-ocular pressure in a patient with open
angle glaucoma/ocular hypertension not adequately controlled with
monotherapy” be applied to all restricted benefit
listings of all combination eye drops containing an alpha-agonist
(brimonidine) with timolol, a carbonic anhydrase inhibitor
(brinzolamide, dorzolamide) with timolol or a
prostaglandin/prostamide analogue (bimatoprost, latanoprost,
travoprost) with timolol. The PBAC considered that the use of a
combination product in a patient whose elevated intra-ocular
pressure due to open angle glaucoma or ocular hypertension is not
adequately controlled on monotherapy is consistent with current
guidelines which no longer recommend timolol as the first line
therapy for all patients. Comment should be sought from the
sponsors prior to this change being implemented.
The PBAC recommended that the Safety Net 20 day rule should not
apply.
Recommendation:
BRINZOLAMIDE with TIMOLOL MALEATE, eye drops, 10 mg - 5 mg (base)
per mL
(1 % - 0.5 %), 5 mL
Restriction: Restricted Benefit (General and
Optometrical)
Reduction of elevated intra-ocular pressure in a patient with open-angle glaucoma that is not adequately controlled with monotherapy.Reduction of elevated intra-ocular pressure in a patient with ocular hypertension that is not adequately controlled with monotherapy.
Maximum quantity: 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
Alcon agrees to the contents of this PSD.
