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New topical drugs for open-angle glaucoma
  • Relevant BNF section: 11.6

Abstract

When we reviewed the management of open-angle glaucoma in 1997,1 the topical drug treatments available included beta-blockers, a carbonic anhydrase inhibitor (dorzolamide), an alpha2 agonist (apraclonidine), a prostaglandin analogue (latanoprost) and a variety of miotics and sympathomimetics. We concluded that a beta-blocker was the treatment of first choice. Here, we review seven new topical preparations that have been marketed, or had their licensed indications changed, since our earlier article.

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  • Relevant BNF section: 11.6

Background

Glaucoma is the cause of blindness in 12% of those on the England and Wales blind register.2 The most common type in the UK is primary open-angle glaucoma. One risk factor is raised intraocular pressure (IOP), also known as ocular hypertension. However, glaucoma may also develop in people with an IOP in the normal range (12-21mmHg; so-called 'normal tension glaucoma'). Lowering IOP can reduce the risk of optic nerve damage and preserve visual fields, whether or not IOP is raised.3,4 Moreover, the sooner and the greater the fall in IOP, the better the prognosis.4,5

The trials we discuss here all involved patients with either open-angle glaucoma or ocular hypertension. None of the new drugs reviewed is licensed for use in children.

▼Brinzolamide 1% drops

Brinzolamide (pronounced brin-zol-a-my-d; Azopt - Alcon), like dorzolamide, suppresses aqueous humour production by inhibiting the enzyme carbonic anhydrase. Brinzolamide 1% (first marketed in April 2000) is licensed for use alone if beta-blocker monotherapy is inadequate or inappropriate, and for use combined with a beta-blocker. The summary of product characteristics (SPC) recommends one drop two to three times daily. In a randomised trial, brinzolamide (1% two or three times daily) was as effective in lowering IOP as dorzolamide (2% three times daily).6 In a double-blind trial involving 378 patients and lasting 18 months, brinzolamide (1% two or three times daily) was less effective than timolol (0.5% twice daily) (mean reduction in IOP 2.7-3.9mmHg vs. 4.7-5.6mmHg).7

In a randomised placebo-controlled trial lasting 3 months and involving 132 patients with IOP uncontrolled by timolol (0.5% twice daily), addition of brinzolamide (1% three times daily) reduced IOP by an added 3.3-4.1mmHg (vs. 0.9-2.5mmHg with placebo, p=0.03).8 In patients receiving timolol (0.5% twice daily), the additional hypotensive effects of twice-daily brinzolamide 1% or dorzolamide 2% were similar.9

Unwanted effects and contraindications

Transient ocular stinging, blurred vision, headache and bitter taste occur in up to 10% of patients. The stinging is less likely with brinzolamide than with dorzolamide (reported by 2-3% of patients vs. 16% in one trial6). Irreversible corneal oedema has been associated with use of dorzolamide;10 so both dorzolamide and brinzolamide should be used with caution in patients with known or potential endothelial dysfunction. The SPC states that brinzolamide eye drops are contraindicated in patients with severe renal impairment (creatinine clearance below 30mL/minute) or hyperchloraemic acidosis, and are not recommended in pregnant or breast-feeding women.

Brimonidine 0.2% drops

Brimonidine (bri-mo-ni-dean; Alphagan - Allergan) is a selective alpha2 agonist, licensed for use with a beta-blocker or for use alone if beta-blocker monotherapy is inappropriate. The licensed dose of brimonidine 0.2% (first marketed in May 1997) is one drop twice daily. The drug probably lowers IOP both by reducing aqueous humour formation and increasing uveoscleral drainage. In two randomised controlled trials involving a total of 1,320 patients and lasting 12 months, brimonidine (0.2% twice daily) was as effective as timolol (0.5% twice daily) (mean IOP reduction around 4-7mmHg).11,12 The SPC recommends twice-daily administration, although in one study (involving 30 patients) only the three-times-daily (and not the twice-daily) regimen was as effective as timolol (0.5% twice daily) at reducing IOP.13

In a randomised trial, involving 115 patients with IOP inadequately controlled with a topical beta-blocker, addition of either brimonidine (0.2% twice daily) or latanoprost (0.005% once daily) for 3 months, further reduced IOP by similar amounts (around 5mmHg).14 In a randomised trial, 379 patients in whom one or a combination of two drugs had failed to control IOP, switching to monotherapy with latanoprost (0.005% once daily) reduced IOP more than did brimonidine (0.2% twice daily) (mean 7.1mmHg vs. 5.2mmHg).15

Unwanted effects and contraindications

Allergic conjunctivitis (which resolves on stopping the drug) occurred in 12% of patients on brimonidine in a clinical trial lasting 1 year.12 A retrospective study suggests the rate may be as high as 26%.16 Systemic effects include dry mouth, headache, lethargy and drowsiness.

According to the SPC, brimonidine is contraindicated in patients taking a monoamine-oxidase inhibitor or an anti-depressant that affects noradrenergic transmission (e.g. tricyclics, mianserin). It also advises against using the drug in pregnant or breast-feeding women and that it should be used with caution in patients with "severe or unstable and uncontrolled" cardiovascular disease or cerebrovascular insufficiency, Raynaud's syndrome, postural hypotension, thromboangiitis obliterans, depression, or hepatic or renal impairment.

Latanoprost, ▼bimatoprost, ▼travoprost

Latanoprost (la-ta-no-prost; Xalatan - Pharmacia), travoprost (tra-vo-prost; Travatan - Alcon) and bimatoprost (bi-ma-toe-prost; Lumigan - Allergan) are structurally related to prostaglandin F2α. The drugs probably work mainly by increasing uveoscleral drainage. Latanoprost 0.005% had only just been licensed (as a second-line treatment) when we last reviewed glaucoma.1 It is now licensed as a first-line treatment for glaucoma. Bimatoprost 0.03% (first marketed in April 2002) and travoprost 0.004% (first marketed in December 2001) are licensed for use as second-line mono- or adjunctive therapy. For all three, the SPCs recommend one drop daily, in the evening.

Latanoprost 0.005% drops

A meta-analysis of 11 randomised controlled trials (involving a total 1,256 patients) has shown that latanoprost (0.005% once daily), produces an average of 1.6mmHg greater reduction in IOP than does timolol (0.5% twice daily).17 Also, in a 3-month randomised trial involving 224 patients, latanoprost (0.005% once daily) was more effective than dorzolamide (2% three times daily) in reducing IOP (mean reduction 8.5mmHg vs. 5.6mmHg).18 In a meta-analysis, data from nine randomised controlled trials (involving a total of 2,152 patients) that assessed latanoprost or brimonidine, but not against each other, were pooled to compare the two drugs indirectly - a questionable technique.19 On this basis, the authors concluded that latanoprost was more effective at lowering IOP. In a more recently published crossover, double-blind randomised trial involving 33 patients, latanoprost (0.005% once daily for 6 weeks) was more effective than brimonidine (0.2% twice daily for 6 weeks) in reducing mean IOP (fall to 17.6mmHg vs. 15.4mmHg).20 However, in a randomised comparative trial involving 127 patients and lasting 3 months, latanoprost and brimonidine were similarly effective at lowering IOP.21

Latanoprost has additive effects in lowering IOP when used with timolol, pilocarpine, dipivefrin or carbonic anhydrase inhibitors.22

Bimatoprost 0.03% drops

In two randomised, double blind 1-year trials involving 1,198 patients, bimatoprost (0.03% once or twice daily) reduced IOP by more than did timolol (0.5% twice daily) (mean reduction 7.6-8.3mmHg with once-daily vs. 5.1-5.8mmHg with timolol; twice-daily was less effective than once-daily bimatoprost).23 In a randomised 3-month trial involving 232 patients, bimatoprost (0.03% once daily) was as effective as latanoprost (0.005% once daily) in lowering IOP.24 However, in a 6-month randomised trial involving 269 patients, bimatoprost reduced mean IOP by 1.2-2.2mmHg more than did latanoprost.25

Travoprost 0.004% drops

In a randomised trial involving 801 patients and lasting 1 year, travoprost (0.004%) was more effective than timolol (0.5% twice daily) and as effective as latanoprost (0.005% once daily) in reducing IOP (mean reductions of6.6-8.1mmHg vs. 4.7-7.1mmHg vs. 6.2-8.1mmHg, respectively).26 In another two randomised trials, involving a total of 1,178 patients, travoprost (0.004% once daily) caused a greater reduction in IOP than did timolol (0.5% twice daily) (mean reduction 8-8.9mmHg vs. 6.3-7.9mmHg in one study;27 6.5-8mmHg vs. 5.2-7.0mmHg in the other28).

Unwanted effects and contraindications

The three drugs commonly cause minor redness and irritation in the eyes, and darkening, thickening and lengthening of the eyelashes. They can also cause irreversible darkening of the iris (e.g. in 30% of patients on latanoprost), most often in those with mixed-coloured irides (e.g. in up to 85% of those with a yellow-brown iris). The effect, which is more likely when the drug is used for over 6 months, is thought to be due to increased production of melanin rather than by melanocyte proliferation.29 The long-term implications of this are unknown. Although the drugs have not been proven to cause cystoid macular oedema, the SPCs state that they should be used with caution in patients with risk factors for this condition. The SPCs also warn against the use of the drugs in pregnancy and breast-feeding women.

Fixed-combination therapies

Many patients need treatment with more than one drug to achieve the target IOP. Problems can arise, however, when more than one product is administered. For example either or both of the drugs might be diluted or washed out of the eye if the two are administered too closely together in time (leaving at least 5 minutes between doses is therefore recommended); the patient is exposed to more eye-drop preservative (a common cause of intolerance to eye drops); the patient might be confused by the number of bottles; and adherence to the treatments might be affected. The availability of two drugs in one bottle may avoid these problems. However, potential disadvantages of the fixed combinations include the problem of determining which component is causing a local allergic reaction, and that administering the correct dose for one component might involve giving an overdose of the other component.

Two fixed-combination preparations are available in the UK. The unwanted effect profile of both is the same as that of the two constituents used individually.

Cosopt (MSD), which contains dorzolamide 2% and timolol 0.5%, is recommended in the SPC for use at a dose of one drop twice daily. ▼Xalacom (Pharmacia), which contains latanoprost 0.005% and timolol 0.5%, is recommended in the SPC for use at a dose of one drop once daily, in the morning. In clinical trials, both Cosopt30 and Xalacom31 had a greater IOP-lowering effect than either of their individual components used alone.

Conclusion

Lowering intra-ocular pressure (IOP) can arrest progression of glaucoma and, generally, the lower the pressure, the better the prognosis. Several new IOP-lowering drugs have become available over the last few years. Of these, latanoprost, is now an alternative first-line therapy, offering several advantages over timolol, the traditional first-line treatment. It is more effective at lowering IOP, causes fewer systemic unwanted effects, has fewer contraindications and needs to be used only once daily. However, the long-term consequences of its effects on iris pigmentation are not yet known. Also, it costs around four times as much as timolol.

Many patients with glaucoma will require treatment with more than one drug in order to reduce their IOP sufficiently. Fixed-combination drops may be more convenient for these patients and they may also improve adherence, but evidence is needed to prove this. They should be tried only once the individual constituents have been shown to be effective.

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