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 of glaucoma progression by half, so widespread use of latanoprost should be able to delay or prevent vision loss in the vast majority of those who have glaucoma. The table below containing the approximate monthly cost of some of the most frequently used drugs for glaucoma treatment in the US suggests that latanoprost is an extremely cost-effective

option, especially when its efficacy and its ability to be used as both a first-line therapy and as an add-on drug are taken into account. Using GoodRx, a service that compares prices across nationwide pharmacy chains in the US:

Timolol 3

Latanoprost 13

Acetazolamide 13

Dorzolamide (generic Trusopt) 15

Methazolamide 30

Azopt 38

Alphagan P 84

Combigan 87

Travatan Z 96

Acetazolamide ER (generic Diamox Sequels) 101

Xalatan 102

Lumigan 107

Price shown is the lowest price at select nationwide pharmacy chains for a 30-day supply of most-prescribed strength 13. Summary of regulatory status of the medicine (in country of origin, and preferably in other countries as well) Generic latanoprost was approved by the US Food and Drug Administration on March 22, 2011, and generic latanoprost is available in several places, including the US, Europe and India. 14. Availability of pharmacopoeial standards (British Pharmacopoeia, International Pharmacopoeia, United States Pharmacopoeia) Generic latanoprost met United States and Japanese pharmacopoeial standards. 15. Proposed (new/adapted) text for the WHO Model Formulary

Latanoprost, a prostaglandin F2α-analog, has been available for several years in most countries

for the treatment of glaucoma. 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.

From DailyMed:

INDICATIONS AND USAGE

Latanoprost ophthalmic solution is indicated for the reduction of elevated intraocular pressure in

patients with open-angle glaucoma or ocular hypertension.

HOW SUPPLIED

Latanoprost Ophthalmic Solution is a sterile, clear, isotonic, buffered, preserved colorless

solution of latanoprost 0.005% (50 mcg/mL).

DOSAGE AND ADMINISTRATION

The recommended dosage is one drop (1.5 mcg) in the affected eye(s) once daily in the

evening. If one dose is missed, treatment should continue with the next dose as normal.

The dosage of latanoprost ophthalmic solution should not exceed once daily; the combined use

of two or more prostaglandins, or prostaglandin analogs including latanoprost ophthalmic

solution is not recommended. It has been shown that administration of these prostaglandin drug

products more than once daily may decrease the intraocular pressure lowering effect or cause

paradoxical elevations in IOP.

Reduction of the intraocular pressure starts approximately 3 to 4 hours after administration and

the maximum effect is reached after 8 to 12 hours.

Latanoprost ophthalmic solution may be used concomitantly with other topical ophthalmic drug

products to lower intraocular pressure. If more than one topical ophthalmic drug is being used,

the drugs should be administered at least five (5) minutes apart.

CONTRAINDICATIONS

Known hypersensitivity to latanoprost, benzalkonium chloride or any other ingredients in this

product.

PRECAUTIONS

General

Latanoprost ophthalmic solution may gradually increase the pigmentation of the iris. The eye

color change is due to increased melanin content in the stromal melanocytes of the iris rather

than to an increase in the number of melanocytes. This change may not be noticeable for

several months to years. Typically, the brown pigmentation around the pupil spreads

concentrically towards the periphery of the iris and the entire iris or parts of the iris become

more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While

treatment with latanoprost can be continued in patients who develop noticeably increased iris

pigmentation, these patients should be examined regularly.

During clinical trials, the increase in brown iris pigment has not been shown to progress further

upon discontinuation of treatment, but the resultant color change may be permanent.

Eyelid skin darkening, which may be reversible, has been reported in association with the use of

latanoprost.

Latanoprost may gradually change eyelashes and vellus hair in the treated eye; these changes

include increased length, thickness, pigmentation, the number of lashes or hairs and

misdirected growth of eyelashes. Eyelash changes are usually reversible upon discontinuation

of treatment.

Latanoprost should be used with caution in patients with a history of intraocular inflammation

(iritis/uveitis) and should generally not be used in patients with active intraocular inflammation.

Macular edema, including cystoid macular edema, has been reported during treatment with

latanoprost. These reports have mainly occurred in aphakic patients, in pseudophakic patients

with a torn posterior lens capsule or in patients with known risk factors for macular edema.

Latanoprost should be used with caution in patients who do not have an intact posterior capsule

or who have known risk factors for macular edema.

There is limited experience with latanoprost in the treatment of angle closure, inflammatory or

neovascular glaucoma.

There have been reports of bacterial keratitis associated with the use of multiple-dose

containers of topical ophthalmic products. These containers had been inadvertently

contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption

of the ocular epithelial surface.

Contact lenses should be removed prior to the administration of latanoprost and may be

reinserted 15 minutes after administration.

Information for Patients

Patients should be advised about the potential for increased brown pigmentation of the iris,

which may be permanent. Patients should also be informed about the possibility of eyelid skin

darkening, which may be reversible after discontinuation of latanoprost.

Patients should also be informed of the possibility of eyelash and vellus hair changes in the

treated eye during treatment with latanoprost. These changes may result in a disparity between

eyes in length, thickness, pigmentation, number of eyelashes or vellus hairs and/or direction of

eyelash growth. Eyelash changes are usually reversible upon discontinuation of treatment.

Patients should be instructed to avoid allowing the tip of the dispensing container to contact the

eye or surrounding structures because this could cause the tip to become contaminated by

common bacteria known to cause ocular infections. Serious damage to the eye and subsequent

loss of vision may result from using contaminated solutions.

Patients also should be advised that if they develop an intercurrent ocular condition (e.g.,

trauma or infection) or have ocular surgery, they should immediately seek their physician’s

advice concerning the continued use of the multiple-dose container.

Patients should be advised that if they develop any ocular reactions, particularly conjunctivitis

and lid reactions, they should immediately seek their physician’s advice.

Patients should also be advised that latanoprost contains benzalkonium chloride, which may be

absorbed by contact lenses. Contact lenses should be removed prior to administration of the

solution. Lenses may be reinserted 15 minutes following administration of latanoprost.

If more than one topical ophthalmic drug is being used, the drugs should be administered at

least five (5) minutes apart.

Drug Interactions

In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are

mixed with latanoprost. If such drugs are used they should be administered at least five (5)

minutes apart.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Latanoprost was not mutagenic in bacteria, in mouse lymphoma or in mouse micronucleus

tests.

Chromosome aberrations were observed in vitro with human lymphocytes.

Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at

doses of up to 170 mcg/kg/day (approximately 2,800 times the recommended maximum human

dose) for up to 20 and 24 months, respectively.

Additional in vitro and in vivo studies on unscheduled DNA synthesis in rats were negative.

Latanoprost has not been found to have any effect on male or female fertility in animal studies.

Pregnancy

Teratogenic Effects

Pregnancy Category C

Reproduction studies have been performed in rats and rabbits. In rabbits an incidence of 4 of 16

dams had no viable fetuses at a dose that was approximately 80 times the maximum human

dose and the highest nonembryocidal dose in rabbits was approximately 15 times the maximum

human dose. There are no adequate and well controlled studies in pregnant women.

Latanoprost should be used during pregnancy only if the potential benefit justifies the potential

risk to the fetus.

Nursing Mothers

It is not known whether this drug or its metabolites are excreted in human milk. Because many

drugs are excreted in human milk, caution should be exercised when latanoprost is

administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

No overall differences in safety or effectiveness have been observed between elderly and

younger patients.

ADVERSE REACTIONS

Eyelash changes (increased length, thickness, pigmentation and number of lashes); eyelid skin

darkening; intraocular inflammation (iritis/uveitis); iris pigmentation changes; and macular

edema, including cystoid macular edema

Controlled Clinical Trials

The ocular adverse events and ocular signs and symptoms reported in 5% to 15% of the

patients on latanoprost ophthalmic solution in the three 6-month, multicenter, double-masked,

active-controlled trials were blurred vision, burning and stinging, conjunctival hyperemia, foreign

body sensation, itching, increased pigmentation of the iris and punctuate epithelial keratopathy.

Local conjunctival hyperemia was observed; however, less than 1% of the patients treated with

latanoprost required discontinuation of therapy because of intolerance to conjunctival

hyperemia.

In addition to the above listed ocular events/signs and symptoms, the following were reported in

1% to 4% of the patients: dry eye, excessive tearing, eye pain, lid crusting, lid discomfort/pain,

lid edema, lid erythema and photophobia.

The following events were reported in less than 1% of the patients: conjunctivitis, diplopia and

discharge from the eye.

During clinical studies, there were extremely rare reports of the following: retinal artery embolus,

retinal detachment and vitreous hemorrhage from diabetic retinopathy.

The most common systemic adverse events seen with latanoprost were upper respiratory tract

infection/cold/flu, which occurred at a rate of approximately 4%. Chest pain/angina pectoris,

muscle/joint/back pain and rash/allergic skin reaction each occurred at a rate of 1% to 2%.

Clinical Practice

The following events have been identified during post-marketing use of latanoprost in clinical

practice. Because they are reported voluntarily from a population of unknown size, estimates of

frequency cannot be made. The events, which have been chosen for inclusion due to either

their seriousness, frequency of reporting, possible causal connection to latanoprost or a

combination of these factors, include: asthma and exacerbation of asthma; corneal edema and

erosions; dyspnea; eyelash and vellus hair changes (increased length, thickness, pigmentation

and number); eyelid skin darkening; herpes keratitis; intraocular inflammation (iritis/uveitis);

keratitis; macular edema, including cystoid macular edema; misdirected eyelashes sometimes

resulting in eye irritation; dizziness; headache; and toxic epidermal necrolysis.

References

1. Bron, Alain M., and Karl-Heinz Emmerich. "Latanoprost versus combined timolol and

dorzolamide." Survey of ophthalmology 47 (2002): S148.

2. Hedman, Katarina, Peter G. Watson, and Albert Alm. "The effect of latanoprost on

intraocular pressure during 2 years of treatment." Survey of ophthalmology 47 (2002):

S65-S76.

3. Alm, Albert, and Johan Stjernschantz. "Effects on intraocular pressure and side effects

of 0.005% latanoprost applied once daily, evening or morning. A comparison with

timolol. Scandinavian Latanoprost Study Group."Ophthalmology 102.12 (1995): 1743.

4. Camras, Carl B. "Comparison of latanoprost and timolol in patients with ocular

hypertension and glaucoma: a six-month masked, multicenter trial in the United States.

The United States Latanoprost Study Group." Ophthalmology 103.1 (1996): 138.

5. Lusky, Moshe, et al. "A comparative study of two dose regimens of latanoprost in

patients with elevated intraocular pressure." Ophthalmology 104.10 (1997): 1720-1724.

6. Quigley, Harry A. "Glaucoma." Lancet 377.9774 (2011): 1367-1377.

7. Quigley, Harry A., & Broman, Aimee T. "The number of people with glaucoma worldwide

in 2010 and 2020." The British Journal of Ophthalmology 90.3 (2006): 262-7.

8. Alm, Albert, and Ingmar Widengård. "Latanoprost: Experience of 2‐ year treatment in

Scandinavia." Acta Ophthalmologica Scandinavica 78.1 (2000): 71-76.