Section 21 Ophthalmological Preparations Latanoprost - Addition Application submitted by International Council of Ophthalmology 1. Summary statement of the proposal for inclusion, change or deletion We propose the inclusion of latanoprost, a prostaglandin F2α-analog that has been available for over a decade in most countries for the treatment of glaucoma.1 It is one of the most potent and effective agents for the reduction of intraocular pressure currently available for the treatment of adult patients with glaucoma and ocular hypertension.1-5 Latanoprost can be used as a first line therapy, but is also effective in reducing intraocular pressure in combination with other classes of eye medications as well as in cases where other medicines are not effective.1-2 The March 2011 approval of generic latanoprost by the U.S. Food and Drug Administration and the consequent availability over generic latanoprost in other countries has significantly reduced the cost associated with the use of this drug and has made it a very practical option for reducing intraocular pressure in glaucoma and ocular hypertension patients in developing countries. 2. Name of the focal point in WHO submitting or supporting the application (where relevant) Ivo Kocur 3. Name of the organization(s) consulted and/or supporting the application International Council of Ophthalmology 4. International Nonproprietary Name (INN, generic name) of the medicine Latanoprost 5. Formulation proposed for inclusion; including adult and paediatric (if appropriate) Latanoprost 50mcg/ml 6. International availability - sources, if possible manufacturers and trade names Generic latanoprost is available in most countries, including the US, UK, France, Sweden, Ireland, Denmark, Germany, the Netherlands, Finland,Italy, Spain, Iceland, Switzerland, Hungary, Bulgaria, the Czech Republic and India. 7. Whether listing is requested as an individual medicine or as an example of a therapeutic group Individual medicine 8. Information supporting the public health relevance (epidemiological information on disease burden, assessment of current use, target population) Glaucoma is the second leading cause of blindness worldwide. Over 60 million people worldwide are affected by glaucoma, with 8.4 million of them being bilaterally blind.6 By 2020, it is anticipated that nearly 80 million people will be affected by glaucoma.7 In clinical practice, many patients are first treated using eye drops, most often using a prostaglandin analogue such as the proposed drug latanoprost or β-adrenergic antagonists. Pressure lowering is documented to slow the rate of glaucoma progression by half, and if the elevated IOP is left untreated in low and middle income countries, it may lead to severe vision loss. 9. Treatment details (dosage regimen, duration; reference to existing WHO and other clinical guidelines; need for special diagnostics, treatment or monitoring facilities and skills) Generic latanoprost is an eye drop that needs to be administered once a day, preferably in the evening. 10. Summary of comparative effectiveness in a variety of clinical settings: The articles discussed here were chosen because they summarize several notable clinical trials conducted involving latanoprost. A pooled data analysis of three phase III clinical trials conducted in Scandinavia, the UK and the United States showed that latanoprost was able to significantly reduce the mean intraocular pressure in a statistically significantly reduced from the untreated baseline.2 In the 493 patients who were treated for 6 months, latanoprost reduced mean intraocular pressure 8.2 mm Hg and 8.6 mmHg after 0.5 and 6 months of treatment, respectively, from an untreated baseline of 25.8 mm Hg. In the 113 patients who were treated for 2 years, latanoprost reduced mean IOP 8.9 mm Hg 24 months after treatment.2 Morning intraocular pressure at untreated baseline and after 0.5 to 24 months of treatment with latanoprost (mean ± 95% confidence interval, n = number of patients) The intraocular pressure was reduced 15% or more in 93%, 90%, 90%, and 84% of the total number of patients treated with latanoprost for 6, 12, 18, and 24 months, respectively.2 A morning intraocular pressure reduction of about 32% was reached by 50% of the patients treated with latanoprost for 6, 12, 18, and 24 months, respectively.2 Percent patients who reached specific morning intraocular pressure reduction levels (mm Hg) from untreated baseline after 6, 12, 18, and 24 months of latanoprost treatment. For patients who were withdrawn due to insufficient intraocular pressure reduction before specified visits, the last intraocular pressure value on latanoprost was carried forward (n = number of patients). No significant increase in intraocular pressure between the 0.5 month time point and the 24 month time point was observed, suggesting that the efficacy of the latanoprost did not decrease over time. Only 6% of the participants were deemed to have an insufficient intraocular pressure reduction as per the investigator (intraocular pressure treatment failure).2 The overall risk of IOP treatment failure on latanoprost was 8%. Life-table survival function of the risk of treatment failure on latanoprost due to insufficient IOP reduction and of withdrawal due to adverse event (n = number of patients at risk per month). Timolol, the leading topical beta-adrenergic antagonist, is often used as a first line therapy for the treatment of glaucoma. Dorzolamide, the first topical carbonic anhydrase inhibitor to become available on the market, is often prescribed as an add-on therapy. A review of studies comparing the efficacy of latanoprost to combined timolol and dorzolamide suggested that the intraocular pressure lowering effect of latanoprost is equivalent to that of concomitant timolol- dorzolamide therapy. In addition, data suggests that adding latanoprost to timolol and dorzolamide leads to a further 16% reduction of intraocular pressure.1 Meta-analysis of five European studies comparing latanoprost monotherapy with timolol and dorzolamide. Comparison of the IOP reduction in mm Hg at 3 months between treatment groups (mean ± SEM). Percentage of patients who reached a specific reduction in diurnal IOP at 3 months. 11. Summary of comparative evidence on safety*: • Estimate of total patient exposure to date • Description of adverse effects/reactions • Identification of variation in safety due to health systems and patient factors • Summary of comparative safety against comparators Branded Xalatan was the most commonly prescribed glaucoma medication for over a decade and millions of people have been exposed to the drug globally. Almost all side effects are local to the eye and these include conjunctival hyperemia which is almost never severe, iris color change for persons with light colored irides, changes in skin pigmentation, and growth of eyelashes. Ocular irritation also occurs. No systemic side effects are known to be caused by latanaprost (although patient reports occur in clinician studies, these are typically no greater than those reported as a background rate in the study population). A pooled data analysis from two trials showed that the risk of withdrawal from latanoprost before 24 months of treatment as a result of an adverse event was 20%.2 However, in the clinical trials, this included the risk of developing an increase in iris pigmentation. Only 3% of patients were withdrawn due to ocular adverse events other than increased iris pigmentation and 3% due to non-ocular adverse events.2 A detailed breakdown among 255 patients of withdrawals from latanoprost due to adverse events in one of the trials is as below.8 Reasons for withdrawals during 2 years treatment with latanoprost. Patients withdrawn from Group B during the double-masked period then they were on timolol are not included. In a survey of literature comparing latanoprost and combined dorzolamide and timolol treatment, the overall safety profile of latanoprost was found to be as good as that of combined timolol and dorzolamide.1 Adverse event Latanoprost n = 116 Timolol and dorzolamide n = 112 Ocular Eye irritation 27 55 Adverse event Latanoprost n = 116 Timolol and dorzolamide n = 112 Hyperaemia 13 6 Conjunctival disorders 10 5 Blurred vision 3 2 Increased IOP 3 — Epiphora/photophobia 3 2 Blepharitis 2 4 Corneal disorders 2 2 Uveitis 1 — Increased iris pigmentation 1 — Dry eyes 1 — Eye pain — 3 Other 12 2 Non-ocular Respiratory disorders 7 4 Skin disorders 3 2 Influenza-like symptoms 4 3 Metabolic disorder 3 — Cardiovascular disorder 3 — Headache 3 5 Pharyngitis 3 1 Psychiatric disorder 3 1 Gastro-intestinal disorder 1 2 Musculo-skeletal disorder 1 3 Taste perversion — 6 Other 7 4 Adverse Events Reported in the Meta-Analysis of Latanoprost Versus Timolol and Dorzolamide 12. Summary of available data on comparative cost** and cost-effectiveness within the pharmacological class or therapeutic group: • range of costs of the proposed medicine • comparative cost-effectiveness presented as range of cost per routine outcome (e.g. cost per case, cost per cure, cost per month of treatment, cost per case prevented, cost per clinical event prevented, or, if possible and relevant, cost per quality adjusted life year gained) Since latanoprost recently became a generic, the previous data on comparative cost and cost- effectiveness is not valid. Generic latanoprost has been available in India for many years and the cost there is about two dollars per bottle (which lasts a month). Pressure lowering is documented to slow the rate