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Zioptan Receives FDA Approval for Patients with Open-Angle Glaucoma and/or Ocular Hypertension

April 2013 Vol 6 No 3 Payers’ Guide to New FDA Approvals - Select Drug Profiles, Payers' Guide
Loretta Fala
Medical Writer
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Glaucoma is a group of chronic eye diseases that cause irreversible damage to the optic nerve, which leads to serious vision loss and blindness.1 Often associated with increased intraocular pressure, glaucoma affects an estimated 2.2 million people in the United States.1 The population affected by glaucoma is expected to increase to nearly 3 million people by 2020.1 Moreover, glaucoma is projected to become more prevalent as the aging US population increases.2

Glaucoma: Overview
Although there are several types of glaucoma, open-angle glaucoma and angle-closure glaucoma are the 2 main types.3 Other types of glaucoma include normal-tension glaucoma, congenital glaucoma, and several variant forms of the open-angle and angle-closure type, such as secondary glaucoma, traumatic glaucoma, neovascular glaucoma, and others.3 Open-angle glaucoma is the most common type, accounting for approximately ≥90% of all glaucoma cases in the United States.3

Glaucoma is a leading cause of blindness in the United States, accounting for approximately 11% of all cases of blindness.4,5 Blindness resulting from glaucoma is 6 to 8 times more prevalent in blacks than in whites.4 In fact, open-angle glaucoma accounts for 19% of all blindness among blacks compared with 6% of blindness in whites.4 Moreover, the risk of visual impairment is 15 times higher in blacks than in whites.4

Glaucoma is particularly devastating, given its potential to destroy retinal ganglion cells (RGCs) in the optic nerve, which subsequently leads to permanent vision loss.1 Based on recent evidence, increased intraocular pressure may prevent RGCs from receiving a brain-­derived neurotrophic factor, a protein required for RGC survival, from nearby cells in the optic nerve.1

Approximately 70% of patients with glaucoma have a history of elevated intraocular pressure.1 An elevated baseline intraocular pressure has consistently been established as one of the only modifiable risk factors associated with open-angle glaucoma. Other potentially modifiable factors, including intraocular pressure fluctuation and nutrition, are also being researched.6

Vision loss imposes a substantial societal and economic burden for many people in the United States, which results in disability, suffering, and loss of productivity.7 Glaucoma has a detrimental effect on a person’s quality of life—including an effect on driving, walking, and reading—and it also may lead to social withdrawal and depression.2 The economic burden of glaucoma increases as the disease progresses.2 In the United States, glaucoma accounts for an estimated $2.9 billion annually in direct costs alone; this total cost is likely an underestimate, given that many patients with glaucoma are unaware that they have the condition.2,8

Glaucoma remains underdiagnosed and misunderstood.2 Individuals with glaucoma may remain undiagnosed, because the disease is relatively asymptomatic, particularly in the early stages, and a person may not seek medical attention until a bilateral field loss of vision occurs.2 In addition, many patients with diagnosed glaucoma are not receiving treatment.2

Over the past decade, substantial strides have been made in understanding and treating glaucoma.1 The Early Manifest Glaucoma Trial, a 6-year collaborative study, reinforced accumulating medical evidence showing that reducing eye pressure in the early stages of glaucoma slowed the disease progression.1,9 The Ocular Hypertension Treatment Study, an important study that included 1636 participants, showed that topical ocular hypotensive therapy delayed or prevented the onset of primary open-angle glaucoma in patients with elevated intraocular pressure, reducing the development of primary open-angle glaucoma by >50% (P <.001).10 A follow-up to that study showed that the use of daily topical ocular hypotensive therapy reduced the development of primary open-angle glaucoma in black patients by nearly 50% (P = .02).11

Improved screening and diagnostic techniques have led to more precise visual assessment tests. The recent development of prostaglandins, a new class of drugs that provides intraocular pressure control with fewer side effects, has further improved the management of glaucoma.1

Zioptan Receives FDA Approval
In February 2012, the US Food and Drug Administration (FDA) approved Zioptan (tafluprost ophthalmic solution 0.0015%; Merck & Co), a preservative-free prostaglandin analog, to reduce elevated intraocular pressure in patients with open-angle glaucoma, as well as in patients with ocular hypertension (ie, eye pressure), a risk factor for glaucoma.12

Clinical Pharmacology
Tafluprost ophthalmic solution contains tafluprost 0.0015 mg/mL. Tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid metabolite, tafluprost acid. Although its exact mechanism of action is unknown, tafluprost acid, a fluorinated analog of prostaglandin F2α, is a selective prostaglandin F receptor prostanoid receptor agonist that is believed to reduce intraocular pressure by increasing the uveoscleral outflow.

After the administration of 1 drop of the tafluprost 0.0015% solution once daily in each eye of healthy volunteers, the plasma concentrations of tafluprost acid peaked at a median time of 10 minutes on days 1 and 8.

Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is further metabolized through fatty acid β-oxidation and phase 2 conjugation. At 30 minutes after the topical ocular administration of tafluprost 0.0015% ophthalmic solution, the mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytic assay (10 pg/mL).13

Dosing and Use
The recommended dose of tafluprost ophthalmic solution is 1 drop in the conjunctival sac of the affected eye(s) once daily in the evening. The dose should not exceed once daily, because it has been shown that more frequent administration of prostaglandin analogs may lessen the intraocular pressure–lowering effect.

The reduction of intraocular pressure begins approximately 2 to 4 hours after the first administration of tafluprost ophthalmic solution, with the maximum effect reached after 12 hours.13

Tafluprost can be used concomitantly with other topical ophthalmic drugs to lower intraocular pressure. If more than 1 topical ophthalmic agent is being used, each one should be administered at least 5 minutes apart.13

Clinical Studies Data
The FDA’s approval of tafluprost was based on safety and efficacy data from several clinical studies lasting up to 24 months. In these studies, patients with open-angle glaucoma or ocular hypertension and a baseline pressure of 23 mm Hg to 26 mm Hg who received tafluprost, dosed once daily in the evening, showed intraocular pressure reductions between 6 mm Hg and 8 mm Hg at 3 months and between 5 mm Hg and 8 mm Hg at 6 months.13

Table 1
Table 1: Reduction in IOP with Tafluprost versus Timolol: Randomized, Double-Masked Study.

Randomized, Double-Masked, Comparative Study
In a randomized, double-masked, multicenter clinical trial, the efficacy and safety of tafluprost 0.0015% (preservative free) was compared with timolol (Timoptic) 0.5% (preservative free), a nonselective beta-adrenergic receptor antagonist, in 618 patients with open-angle glaucoma or ocular hypertension (Table 1).14 This study demonstrated that the intraocular pressure–lowering effect of tafluprost was noninferior to that of timolol.14

After hypotensive treatment was discontinued or washed out, patients with intraocular pressure between ≥23 mm Hg and ≤36 mm Hg in at least 1 eye were randomized in a 1:1 ratio to 12 weeks of therapy with tafluprost 0.0015% or with timolol 0.5%. Intraocular pressure measurements were taken 3 times throughout the day at baseline and at weeks 2, 6, and 12. At each of the 9 assessment time points, the study was powered for a noninferiority margin of 1.5 mm Hg.14

Patient-reported ocular pain, stinging, and irritation were similar in the tafluprost and the timolol groups (4.4% vs 4.6%, respectively). The percentages of patients who reported conjunctival hyperemia were 4.4% for tafluprost and 1.2% for timolol (nominal P = .16).14

Table 2
Table 2: Reduction in IOP in All Patients Treated with Tafluprost: Observational Study.


Table 3
Table 3: IOP Reduction in Subgroups of Patients Switched to Tafluprost Monotherapy: Observational Study.

Observational Study with a Large Patient Population
Another study evaluated the efficacy, local tolerability, and safety of preservative-free tafluprost of 2123 patients with ocular hypertension and glaucoma (Table 2).15 Tafluprost significantly reduced intraocular pressure in all patients and also significantly reduced intraocular pressure in all monotherapy subgroups (Table 3).15

Medication changes were made in 41.1% of the patients because of tolerability issues and in 25.6% of the patients because of insufficient efficacy with previous medication.15 After changing these patients’ medication to tafluprost, their tolerability to the treatment improved. At the final visit, 85.7% of the patients rated their tolerability to the treatment as good or very good.15 The reasons for switching therapy to or adding preservative-free tafluprost included local intolerance (41.1%) and efficacy (25.6%), among other reasons. No details for the reason of changing or adding therapy were available for 16.4% of the patients.

During the treatment period, there were only a few adverse events. After the final visit, 97.8% of the patients continued treatment with tafluprost. Treatment was discontinued in 18 patients because of local intolerance, in 6 patients because of efficacy issues, in 4 patients who reported systemic side effects, and in 2 patients who preferred using a multidose treatment regimen.15

Safety Profile and Metabolic Properties
Tafluprost 0.0015% was evaluated in 905 patients in 5 controlled clinical studies of up to 24 months. In patients treated with tafluprost, the most frequent adverse reaction was conjunctival hyperemia, which was reported in a range of 4% to 20% of the patients. Approximately 1% of the patients discontinued therapy because of ocular adverse reactions.13

Ocular adverse reactions reported in clinical studies (incidence, ≥2%) include13:

  • Ocular stinging or irritation, 7%
  • Ocular pruritus, including allergic conjunctivitis, 5%
  • Cataract, 3%
  • Dry eye, 3%
  • Ocular pain, 3%
  • Eyelash darkening, 2%
  • Growth of eyelashes, 2%
  • Blurred vision, 2%.

The nonocular adverse reactions reported (incidence, 2%-6%) include:

  • Headache, 6%
  • Common cold, 4%
  • Cough, 3%
  • Urinary tract infection, 2%.

Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F2α analogs. Tafluprost should be used with caution in patients with aphakia, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema.

Adverse reactions reported in postmarketing studies include iritis and uveitis. In postmarketing use with prostaglandin analogs, periorbital and lid changes, including deepening of the eyelid sulcus, have been observed.13

Precautions and Warnings
There are no contraindications associated with the use of tafluprost. Changes to pigmented tissues, including pigmentation of the iris, eyelid, and eyelashes, have been reported with tafluprost use. Pigmentation is expected to increase as long as tafluprost is administered. After tafluprost is discontinued, pigmentation of the iris is likely to be permanent, whereas eyelid pigmentation and eyelash changes have been reported to be reversible in some patients.

Tafluprost may gradually change eyelashes and vellus hair in the treated eye. These changes, which include increased length, color, thickness, shape, and number of lashes, are usually reversible when the treatment is discontinued.

Tafluprost should be used with caution in patients with active intraocular inflammation, because inflammation may be exacerbated.13

Specific Populations
There are no adequate and well-controlled studies of tafluprost in pregnant women. Tafluprost should not be used during pregnancy unless the potential benefit justifies the potential risk to the fetus. It is not known whether tafluprost or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when tafluprost is given to a woman who is breastfeeding.13

No overall clinical differences in safety or effectiveness of tafluprost have been observed between elderly and other adult patients using this medication. Tafluprost is not recommended for use in pediatric patients because of the potential safety concerns related to increased pigmentation after long-term, chronic use.13

Conclusion
With the FDA approval of tafluprost in 2012, another treatment option became available for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension—serious conditions that can lead to blindness. Tafluprost ophthalmic solution, a preservative-free prostaglandin analog, was shown to be effective, safe, and generally well tolerated in a broad patient population in several studies lasting up to 24 months.16 Patients with open-angle glaucoma or with ocular hypertension who received tafluprost once daily demonstrated reductions in intraocular pressure and improved eye health outcomes.

References

  1. National Institutes of Health. NIH Fact Sheets—Glaucoma. Updated February 14, 2011. http://report.nih.gov/nihfactsheets/ViewFactSheet.aspx?csid=92. Accessed January 28, 2013.
  2. Varma R, Lee PP, Goldberg I, Kotak S. An assessment of the health and economic burdens of glaucoma. Am J Ophthalmol. 2011;152:515-522.
  3. Glaucoma Research Foundation. Types of glaucoma. Updated May 24, 2012. www.glaucoma.org/glaucoma/types-of-glaucoma.php. Accessed January 28, 2013.
  4. Glaucoma Research Foundation. Glaucoma facts and stats. Updated May 24, 2012. www.glaucoma.org/glaucoma/glaucoma-facts-and-stats.php. Accessed January 28, 2013.
  5. Kymes SM, Plotzke MR, Li JZ, et al. The increased cost of medical services for people diagnosed with primary open-angle glaucoma: a decision analytic approach. Am J Ophthalmol. 2010;150:74-81.
  6. Coleman AL, Miglior S. Risk factors for glaucoma onset and progression. Surv Ophthalmol. 2008;53(suppl 1):S3-S10.
  7. Centers for Disease Control and Prevention. Vision Health Initiative—basic information: fast facts. Updated February 5, 2009. www.cdc.gov/visionhealth/basic_ information/fast_facts.htm. Accessed January 28, 2013.
  8. Rein DB, Zhang P, Wirth KE, et al. The economic burden of major adult visual disorders in the United States. Arch Ophthalmol. 2006;124:1754-1760.
  9. Heijl A, Leske MC, Bengtsson B, et al. Early Manifest Glaucoma Trial Group. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120:1268-1279.
  10. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;12:701-713;discussion 829-830.
  11. Higginbotham EJ, Gordon MO, Beiser JA, et al; the Ocular Hypertension Treatment Study Group. The Ocular Hypertension Treatment Study: topical medical delays or prevents primary open-angle glaucoma in African American individuals. Arch Ophthalmol. 2004;122:813-820.
  12. US Food and Drug Administration. FDA approves Zioptin to treat elevated eye pressure. FDA News Release. February 14, 2012. www.fda.gov/NewsEvents/News room/PressAnnouncements/ucm291966.htm. Accessed January 28, 2013.
  13. Zioptan (tafluprost ophthalmic solution) 0.0015% [package insert]. Whitehouse Station, NJ: Merck and Co, Inc; 2012.
  14. Chabi A, Varma R, Tsai JC, at al. Randomized clinical trial of the efficacy and safety of preservative-free tafluprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2012;153:1187-1196.
  15. Erb C, Lanzl I, Seidova SF, Kimmich F. Preservative-free tafluprost 0.0015% in the treatment of patients with glaucoma and ocular hypertension. Adv Ther. 2011;28: 575-585.
  16. Pozarowska D. Safety and tolerability of tafluprost in treatment of elevated intraocular pressure in open-angle glaucoma and ocular hypertension. Clin Ophthalmol. 2010;4:1229-1236.
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Last modified: May 28, 2013
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