Brinzolamide with brimonidine tartrate (Simbrinza): Restricted Benefit listing

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

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

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

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.

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