From 1 December 2015 brinzolamide with brimonidine tartrate fixed-dose combination (Simbrinza) is listed on the PBS for adults with either open-angle glaucoma or ocular hypertension who are not achieving adequate control of intraocular pressure with monotherapy.1
The Pharmaceutical Benefits Advisory Committee recommended listing brinzolamide/brimonidine combination therapy on a cost-minimisation basis against a mixed comparator of dorzolamide/timolol FDC (the least expensive of the PBS-listed timolol FDCs) and the individual components of brinzolamide and brimonidine.1
Evidence from the main clinical trial2, 3 submitted to the PBAC demonstrated that the brinzolamide/brimonidine FDC had similar efficacy and safety to that of concomitant use of brinzolamide and brimonidine.
Box 1 Open-angle glaucoma or ocular hypertension1
Open-angle glaucoma involves changes to the optic nerve head and defects to the vision field, usually with raised intra-ocular pressure (IOP).
In open-angle glaucoma the root of the iris does not block the angle of the eye’s anterior chamber as it does in angle-closure glaucoma.
Ocular hypertension is defined as consistent or recurrent IOP that is > 21 mmHg, without clinical evidence of optic nerve damage or visual field defect.1
About the product
Brinzolamide with brimonidine tartrate is an FDC of eye drops that contains both a carbonic anhydrase inhibitor and an alpha-2-adrenergic receptor agonist.4
Both active ingredients lower IOP by suppressing the formation of aqueous humour from the ciliary process in the eye, though they have different mechanisms of action.4
Place in therapy
Elevated IOP is a strong modifiable risk factor for the development and progression of open-angle glaucoma. For every 1 mmHg reduction in IOP, risk of glaucoma progression drops by about 10%.5
For both open-angle glaucoma and ocular hypertension, first-line therapy is a prostaglandin analogue or beta-blocker monotherapy. If these therapies do not adequately control IOP, monotherapy with brimonidine or brinzolamide are among the second-line treatment options.6
According to NHMRC guidelines combination therapies are considered last-line therapy.6
Lack of adherence to medication is a significant problem among patients with glaucoma. To combat this, Australian guidelines advise simplifying the medication regimen ‘wherever possible’.6
Previous research has suggested that adding additional medications might lead to reduced adherence to the initial therapy.9
Brinzolamide/brimonidine FDC is no less effective (non-inferior) than concomitant use of brinzolamide and brimonidine
The mean difference in the primary outcome – change in diurnal IOP – between the two groups was –0.1 mmHg (95% CI : –0.5 to 0.2 mmHg).2
This meets the criteria for non-inferiority, as defined in the study and accepted by the PBAC, as the upper limit on the confidence interval of the ‘between-group difference’ is < 1.5 mmHg.2
The combination therapy is more effective than the individual components used as monotherapy.10
However, the results of the indirect comparison between brinzolamide/brimonidine FDC11
There were differences between the trial populations, as well as differences in the mean reduction of IOP for the patients taking brinzolamide monotherapy.
The sponsor argued these ‘exchangeability issues’ precluded a meaningful comparison.1
But while there were no statistically significant differences in comparative effectiveness between the treatments, brinzolamide/brimonidine FDC consistently failed to meet the non-inferiority criteria, as the upper confidence intervals exceeded + 1.5 mmHg.9-11
Box 2 Basis of PBS listing
The PBS listing was based on data from1:
- one head-to-head randomised trial that compared brinzolamide/brimonidine FDC with brinzolamide and brimonidine administered separately 10 minutes apart (n = 888). 3 This was the main comparator.
- a randomised trial comparing brinzolamide/brimonidine FDC with either brinzolamide or brimonidine alone (n = 560).10
- an indirect qualitative comparison of brinzolamide/brimonidine FDC with brinzolamide/timolol FDC (Azarga)10. The common reference was brinzolamide monotherapy, based on one randomised trial from 2008 (n = 523).11
The head-to-head trial showed brinzolamide/brimonidine FDC was as safe as brinzolamide and brimondine administered concomitantly (Table 1).3
The supportive trial found the safety profile was also non-inferior to that of brimonidine alone, though inferior to brinzolamide monotherapy.10
The most common adverse reactions seen in the two key trials were local. They included:9
- ocular or conjunctival hyperaemia
- blurred vision
- ocular allergies (eg, allergic conjunctivitis)
- eye discomfort or pain.
The most common systemic adverse reactions included dysguesia, dry mouth, drowsiness and fatigue.9
Table 1 Comparison of adverse events of brinzolamide/brimondine FDC vs concomitant use brinzolamide and brimondinea
Concomitant brinzolamide + brimondine
Total, serious adverse events
Treatment-related adverse events
Discontinued because of adverse events
Based on data from the head-to-head trial3
Ongoing monitoring is an important part of anti-glaucoma care, particularly after starting a new medicine.
The side-effect profile of brinzolamide/brimonidine FDC is consistent with that of the two active ingredients, brimonidine tartrate and brinzolamide.10
Increased monitoring and caution is recommended for patients:4
- who wear contact lenses or have compromised corneas (eg, patients with diabetes mellitus or corneal dystrophies) because carbonic anhydrase inhibitors may affect corneal hydration
- taking antihypertensives and/or cardiac glycosides or who have severe or unstable and uncontrolled cardiovascular disease – some patients have experienced small decreases in blood pressure
- at risk of renal impairment – due to possible risk of metabolic acidosis
- taking tricylcic antidepressants; these can lessen the therapeutic response
- taking medicines that can affect the metabolism and uptake of circulating amines
- with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension or thromboangiitis obliterans
- with frequent and prolonged use – monitor carefully for keratopathies. Symptoms of keratopathy can include foreign body sensation, photophobia and decreased visual acuity.
Inconsistencies between trial populations and patients the medicine is listed for
The current PBS listing is for patients with open-angle glaucoma or ocular hypertension whose elevated IOP is not adequately controlled using monotherapy.1
However, the two main trials included not only patients the investigator subjectively assessed as ‘insufficiently controlled on monotherapy’ but also those already taking multiple IOP-lowering medications.10
No information on the proportion of patients on monotherapy versus combination therapy, or which medicines they were taking before enrolment, has been reported. Patients were not taking any therapy at baseline due to a washout period.10
- Australian Government Department of Health. Public Summary Document. Brinzolomide with Brimonidine (Simbrinza). July 2015 PBAC meeting. [PBS] (accessed 3 November 2015).
- Gandolfi SA, Lim J, Sanseau AC, et al. Randomized trial of brinzolamide/brimonidine versus brinzolamide plus brimonidine for open-angle glaucoma or ocular hypertension. Adv Ther 2014;31:1213-27. [PubMed]
- Alcon Research. Brinzolamide/Brimonidine Twice a Day (BID) Fixed Combination (FC) vs Brinzolamide BID Plus Brimonidine BID in Patients With Open Angle Glaucoma or Ocular Hypertension. 2014. [ClinicalTrials.gov] (accessed 3 September 2015).
- Alcon Laboratories (Australia) Pty Ltd. Product Information: SIMBRINZA\u00ae (brinzolamide 1% & brimonidine tartrate 0.2%) Eye Drops. 2015. [TGA] (accessed 3 September 2015).
- Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol 2002;120:1268-79. [PubMed]
- National Health & Medical Research Council. NHMRC Guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma 2010. 2010. [NHMRC] (accessed 3 September 2015).
- Robin AL and Covert D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? Ophthalmology 2005;112:863-8. [PubMed]
- Nguyen QH. Combination of brinzolamide and brimonidine for glaucoma and ocular hypertension: critical appraisal and patient focus. Patient Prefer Adherence 2014;8:853-64. [PubMed]
- Aung T, Laganovska G, Hernandez Paredes TJ, et al. Twice-daily brinzolamide/brimonidine fixed combination versus brinzolamide or brimonidine in open-angle glaucoma or ocular hypertension. Ophthalmology 2014;121:2348-55. [PubMed]
- Alcon Research. Brinzolamide/Brimonidine Twice a Day (BID) Fixed Combination (FC) vs Brinzolamide BID and Brimonidine BID in Patients With Open Angle Glaucoma or Ocular Hypertension. 2014. [ClinicalTrials.gov] (accessed 3 September 2015).
- Kaback M, Scoper SV, Arzeno G, et al. Intraocular pressure-lowering efficacy of brinzolamide 1%/timolol 0.5% fixed combination compared with brinzolamide 1% and timolol 0.5%. Ophthalmology 2008;115:1728-34, 34 e1-2. [PubMed]