Latanoprost with Timolol Maleate, eye drops, 50 micrograms-5 mg (base) per mL (0.005%-0.5%), 2.5 mL, Xalacom®. , July 2005

Public Summary Document for Latanoprost with Timolol Maleate, eye drops, 50 micrograms-5 mg (base) per mL (0.005%-0.5%), 2.5 mL, Xalacom®. , July 2005.

Page last updated: 24 October 2005

Public Summary Document
Product: Latanoprost with Timolol Maleate, eye drops, 50 micrograms-5 mg (base) per mL (0.005%-0.5%), 2.5 mL, Xalacom®.
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: July 2005

1. Purpose of Application

This application sought listing on the Pharmaceutical Benefits Scheme (PBS) as a restricted benefit for the reduction of elevated intraocular pressure in certain patients with open-angle glaucoma and ocular hypertension.

2. Background

This is the second application for PBS listing of this product. A submission for Xalacom was rejected by the PBAC its September 2001 meeting due to insufficient evidence of additional benefit of the combination over Latanoprost monotherapy.

3. Registration Status

Xalacom is registered by the Therapeutic Goods Administration for “the reduction of elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension who are insufficiently responsive to beta-blockers, prostaglandins or other intraocular pressure lowering medications. Xalacom should not be used to initiate therapy.”

4. Listing Requested and PBAC’s View

The sponsor requested the following listing:

Restricted Benefit
For the reduction of elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension who are insufficiently responsive to beta-blockers, prostaglandins or other intraocular pressure lowering medication.

Following advice from the PBAC’s Restrictions Working Group the PBAC noted that the sponsor modified the requested listing to read:

Restricted Benefit
Reduction of elevated intraocular pressure in patients with open-angle glaucoma who are not adequately controlled with Timolol Maleate 5 mg (base) per mL (0.5%) (bd) eye drops and who are insufficiently responsive to prostaglandins or other intraocular pressure lowering medication.
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 and who are insufficiently responsive to prostaglandins or other intraocular pressure lowering medication.

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 nominated the unfixed combination of Latanoprost and timolol (these two mono-therapies used in combination). This was considered appropriate by the PBAC.

7. Clinical Trials

The submission presented the results of two key trials (Trials 036 and 018), and two supportive trials (Trials 004 and 005).

Three of these studies had been published at the time of submission, as follows:

Trial/first author	Protocol title	Publication citation
018/ Diestlehorst M	A 12-week cross-over study comparing the fixed combination of Latanoprost and Timolol Maleate with the concomitant use of the individual components in patients with open angle glaucoma and ocular hypertension.	British Journal of Ophthalmology 2004; 88(2):199-203.
004/ Pfeiffer, N	A comparison of the fixed combination of Latanoprost and timolol with the individual components.	Greafes Archive for Clinical and Experimental Ophthalmology 2002; 240(11):893-9.
005/ Higginbotham EJ	Latanoprost and timolol combination therapy versus monotherapy: one year randomised trial.	Archives of Ophthalmology 2002; 120:915-22.

 

8. Results of Trials

The pre-specified non-inferiority criterion for the combination and the two components administered separately was met for Trial 036, but was not met for Trial 018.

In Trial 036, Latanoprost plus Timolol Maleate fixed combination administered once daily, was non-inferior to concomitant Latanoprost 0.005% once daily and Timolol Maleate 0.5% eye drops twice daily. This was on the basis of mean diurnal intraocular measurements and that a non-inferiority margin of 1.5 mmHg is taken to define a minimal clinically important difference in intraocular pressure reduction.

Supportive Trials 004 and 005 demonstrated statistically significant greater reductions in mean diurnal intraocular pressure of Latanoprost and Timolol Maleate fixed combination (daily) compared to Latanoprost monotherapy.

The submission presented new toxicity data, which showed that Xalacom has similar or less toxicity compared to the individual components administered separately.

For further information on PBAC’s view on the results of clinical trials, see Recommendations and Reasons.

9. Clinical Claim

The submission claimed that Latanoprost plus Timolol Maleate fixed combination eye drops daily is no worse than concomitant Latanoprost daily and Timolol Maleate eye drops twice daily in terms of effectiveness and has similar or less toxicity.

10. Economic Analysis

A cost-minimisation analysis was presented based on the current prices-to-pharmacist of the single agents.

11. Estimated PBS Usage and Financial Implications

The submission estimated the financial cost to the PBS to be < 10 million per year by year four of PBS listing.

12. Recommendation and Reasons

The PBAC accepted that, overall, the data support the conclusion that Latanoprost plus Timolol Maleate fixed combination once daily is non-inferior to concomitant Latanoprost 0.005% once daily and Timolol Maleate 0.5% eye drops twice daily on the basis of mean diurnal intraocular pressure measurements and a non-inferiority margin of 1.5 mmHg is taken to define a minimal clinically important difference in intraocular pressure reduction. This conclusion rests primarily on Trial 036, but is not inconsistent with Trial 018 if the non-inferiority margin of 1.5 mmHg is accepted rather than the pre-specified margin of 1.0 mmHg and account is taken of the arguments emphasised in the Pre-PBAC Response about a superior Latanoprost effect when administered in the evening rather than in the morning. It was noted that, in Trial 018, the combination therapy was administered in the morning while Latanoprost therapy was administered in the evening when given concomitantly with Timolol Maleate twice daily, whereas in Trial 036, the combination therapy and the Latanoprost part of the concomitant therapy were both administered at the same time - in the evening. The PBAC thus accepted the submission’s claim that Latanoprost plus Timolol Maleate fixed combination eye drops once daily is no worse than concomitant Latanoprost once daily and Timolol Maleate eye drops twice daily in terms of effectiveness and has similar or less toxicity.

The submission did not satisfactorily address the PBAC’s concern that there was insufficient evidence of a clinically important improvement in effectiveness with this combination by adding Timolol Maleate to Latanoprost administered once daily. Supportive Trials 004 and 005 both demonstrated statistically significant reductions in mean diurnal intraocular of Latanoprost plus Timolol Maleate fixed combination once daily over Latanoprost monotherapy once daily. However, the point estimates of -1.2 mmHg and -1.0 mmHg respectively are less than the non-inferiority margin of 1.5 mmHg accepted above, suggesting that the detected differences are not clinically important. The PBAC also noted that, in Trial 005, the combination therapy was administered in the morning while Latanoprost monotherapy was administered in the evening, whereas in Trial 004, the combination and the monotherapy were both administered at the same time - in the morning. No new trials were presented in the current submission comparing the combination therapy with Latanoprost monotherapy. However, the Pre-PBAC Response provided an abstract of a new small (N=37) randomised cross-over trial by Konstas et al comparing evening versus evening doses for the combination versus Latanoprost monotherapy, which demonstrates a 2.5 mmHg increase for the combination over Latanoprost monotherapy.

The PBAC agreed that a reduction in intraocular pressure of greater than 1.5 mmHg is clinically relevant, but noted that the extent of further intraocular pressure reduction reported in the Konstas trial conflicts with those of the larger Trials 004 and 005. The PBAC deferred a decision on the listing to request that the sponsor provide a meta-analysis of Trial 004 and the Konstas trial. (accepting that Trial 005 could be excluded because the eye drops were administered at different times in the day, which might confound the extent of the additional effect of Timolol Maleate, and noting that no argument is presented by the sponsor to suggest that the effect of Timolol Maleate is similarly influenced by whether it is given in the morning or the evening). If there are sound arguments not to meta-analyse these two trials, then the PBAC would be prepared to consider what arguments might be presented to justify relying on a comparison of evening administration over a comparison morning administration. The PBAC would also be prepared to re-consider the basis for determining the minimal clinically important difference, but noted that an argument to reduce it from 1.5 mmHg to 1.0 mmHg might raise questions about the basis of the PBAC’s above acceptance of the non-inferiority of the combination product and its two components given concomitantly.

Recommendation:
Defer

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