The U.S. Food and Drug Administration (FDA) regulates 25% of expenditures by American consumers—including most food products (excluding meat and poultry), human and animal medications, medical devices, cosmetics, animal feedstuffs and radiation-emitting products for consumer use. The FDA, which originated in 1862 as part of the U.S. Department of Agriculture, became the Food, Drug and Insecticide Administration in 1927.1 However, it was the Food, Drug and Cosmetic Act of 1938 that strengthened the regulatory powers of the FDA and mandated pre-approval of new medications and prohibited false therapeutic claims for drugs.2
The Center for Drug Evaluation and Research (CDER), a subdivision of the FDA, is responsible for ensuring that drugs marketed in the U.S. are safe and effective. Drug developers begin the approval process by submitting an Investigational New Drug (IND) application to CDER. Molecules that may eventually become FDA-approved medications must undergo a rigorous, multi-step evaluation process that demonstrates efficacy and safety.3
Some medications used in other countries may be available in the U.S.; however, not all these drugs have received FDA approval. Others might currently be under review with the FDA. In this article, I will examine some of the ophthalmic medications and devices that are available globally, but are not yet approved for use in the U.S.
In some categories of ophthalmic medications, the list of globally available agents is virtually identical to the U.S.-approved formulary––but this is not true in the case of glaucoma medications.
A good example of a “global drug” is
tafluprost, a prostaglandin analog marketed by Santen Pharmaceuticals as
Taflotan (European countries) and Tapros (Japan).4 In
limited areas of Western Europe (excluding Germany), North America,
South America and Africa, Merck Pharmaceuticals has contracted with
Santen to market tafluprost under the trade name Saflutan: this
medication is available in both preserved and preservative-free
In a review article, Dorota Pozarowska of the Department of Ophthalmology at the Medical University of Lublin, Poland, summarized the results of several studies involving tafluprost.6 Its ocular hypertensive effects are very similar to latanoprost and, like other prostaglandin analogues, it causes changes in lid and iris pigmentation in approximately 25% of individuals.6 Currently, tafluprost is being tested for the “reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension” in Phase 3 clinical trials.7
many instances, a single medication may not reduce intraocular pressure
to targeted levels and fixed combination medications may provide a
convenient alternative. Using one drop to deliver two types of drugs
simplifies the regimen and reduces exposure to preservatives. Several
fixed combination glaucoma medications that are currently available
abroad are not approved in the U.S.:
• Santen Pharmaceuticals markets two products: the twice-daily Fotil (timolol 0.5% and pilocarpine 2.0%) and Fotil Forte (timolol 0.5% and pilocarpine 4.0%). The medication lowers pressure by reducing aqueous production and increasing trabecular outflow. Finnish researchers found that after 10 weeks of dosing, Fotil decreased mean daily intraocular pressure by 7.48mm Hg. Seventy of 89 subjects reported side effects—11 of which were severe enough to warrant discontinuation from the study.8
• Proksofelin (1% proxodolol and 0.25%
clonidine, Moscow Research Institute of Eye Diseases) is a topical
anti-glaucoma solution used in Russia. Proxodolol is a beta-adrenergic
blocking agent with alpha-adrenergic blocking properties.9,10
Clonidine is an alpha-agonist agent used systemically to treat
hypertension, dysmenorrhea and ADHD. It is chemically similar to—but
reported to be less selective than—bromonidine.11 Proksofelin
is dosed two to three times per day. It is contraindicated in
individuals with asthma, chronic obstructive pulmonary disease (COPD),
heart block and heart failure. Intraocular pressure reduction reportedly
results from decreased anterior chamber outflow (50% to 70%) and by
lowering of aqueous production (45% to 50%).
• DuoTrav (timolol maleate 0.5% and travoprost 0.004%, Alcon) is produced and marketed in Europe, Australia and Canada. It is preserved with Polyquad. Both components reduce intraocular pressure by limiting aqueous production. Bret Hughes, M.D., and colleagues compared DuoTrav instilled in the morning to concomitant therapy dosing timolol 0.5% in the morning and travaprost 0.004% in the evening. They found that subjects using DuoTrav had mean IOP reductions from baseline ranging from 7.4mm Hg to 9.4mm Hg. Subjects taking the concomitant therapy had pressure reductions ranging from 8.4mm Hg to 9.4mm Hg.12
Alcon submitted DuoTrav (under the trade name Extravan) to the FDA for approval in the U.S. and received an approvable letter in September 2004. To date, however, Extravan has not received approval. The reported advantages of DuoTrav over concomitant therapy include convenience (fewer bottles and drops per day), improved compliance, cost savings (fewer co-payments) and elimination of potential washout effects.
• Xalacom (timolol maleate 0.5% and latanoprost 0.005%, Pfizer) is currently available in Europe and parts of South America. The FDA is reviewing the drug under the trade name Xalcom. Italian researchers compared the use of separately dosing timolol and latanoprost and the fixed combination product. They found IOP was significantly decreased (from 18.3mm Hg +/- 2.9mm Hg) to 16.6mm Hg +/- 2.7mm Hg) after substitution (p < 0.0001) of the combination product and 82% of patients reached an IOP <18mm Hg (p < 0.0001).13 Use of the combination product resulted in a significant improvement in TFBUT p<0.0001.
Eve Higginbotham, M.D., and colleagues conducted a similar study and found that at week 26, diurnal IOP levels were at 19.9mm Hg in the Xalcom group. In contrast, pressures were 20.8mm Hg in the latanoprost-only group and 23.4mm Hg in the timolol-only treated patients.14 These studies suggest that Xalcom would be a useful tool in managing ocular hypertension and glaucoma.
• Azarga (brinzolamide 1% and timolol
0.5%, Alcon) is preserved with Polyquad, in lieu of BAK. German
researchers conducted a study of over 14,000 subjects and discovered
that Azarga produced better pressure lowering than previous regimens and
were well tolerated.15
In addition to glaucoma medications, there have been several recent advances in the surgical management of glaucoma.
The iStent (Glaukos) is a very small device made of surgical grade titanium. It weighs 60µg and features dimensions of 0.5mm x 0.25mm x 1.0mm. Open-angle glaucoma is believed to result from an abnormality of the trabecular meshwork, which creates resistance to outflow and hence elevated intraocular pressure. The surgeon utilizes a conjunctival-scleral approach to implant the iStent in Schlemm’s canal, typically in the lower nasal quadrants where there are numerous collector channels. The device creates patent communication between Schlemm’s canal and the anterior chamber, bypassing the trabecular meshwork and re-establishing physiologic intraocular pressure. The iStent is approved for select countries in Europe as well as Canada. It is currently under FDA review.
The CyPass Micro-Stent (Transcend
Medical) is a very small tube that is inserted in the eye during routine
cataract surgery. It is designed to enhance uveoscleral outflow and is
implanted immediately after the intraocular lens (IOL) is positioned in
the eye. Using specialized instrumentation, the CyPass Micro-Stent is
placed in the suprachoroidal space of the ciliary body to create a new
route for uveoscleral drainage of fluid, thereby reducing intraocular
Dry Eye Treatment
A survey of the literature shows that many of the products used for dry eye disease are available in the U.S. and abroad.
One exception, however, is diquafosol tetrasodium ophthalmic solution—the first P2Y2 receptor agonist to be formulated as an ophthalmic solution. Inspire Pharmaceuticals filed a New Drug Application (NDA) for Prolacria (diquafosol tetrasodium) for the treatment of dry eye in 2003 and received an approvable letter in December 2003. However, after several additional clinical trials, the application was denied. Diquas (diquafosol tetrasodium 3%, Santen Pharmaceuticals) was approved in Japan in April 2010 as a treatment for dry eye. Inspire Pharmaceuticals has since been acquired by Merck and there are no current FDA trials for diquafosol.
Another notable dry eye product is Hyalein (sodium hyaluronate ophthalmic solution 0.1% and 0.3%, Santen Pharmaceuticals). This product is reported to aid in the bonding and repair of corneal epithelial cells. It helps cure corneal injuries, retain and stabilize tears to prevent eyes from drying out. This product is currently unavailable in the U.S.
The approval process for medications and
devices differs throughout the world. In some cases, the FDA has
repeatedly declined to approve medications that have been accepted in
other countries—for example, diquafosol. Other drugs simply have never
been submitted to the FDA for approval, perhaps because the road to
approval is not easy. In fact, in the past 10 years, just 10 medications
have been approved under the general category of ophthalmology. Yet, we
have only touched on a small segment of medications that may
potentially be approved for use in the U.S.
William Townsend, O.D., is a graduate of the University of Houston College of Optometry and practices in a multi-location setting. He is Distinguished Visiting Clinician in Residence, an adjunct professor at the University of Houston College of Optometry and the current president of the Ocular Surface Society of Optometry.
1. Swann. JP. The FDA’s Origins & Functions. FDA. 2009 Jun. Available at:
www.fda.gov/aboutFDA/WhatWeDo/History/Origin (accessed July 2011).
2. Part II-The 1938 Food, Drug, and Cosmetic Act. FDA. 2009 Jun. Available at: www.fda.gov/AboutFDA/WhatWeDo/History/Origin/ucm054826.htm (accessed July 2011).
3. About the Center for Drug Evaluation and Research. FDA. 2011 Aug. Available at: www.fda.gov/AboutFDA/CentersOffices/CDER/default.htm (accessed August 2011).
4. Santen Pharmaceutical. Santen and Merck & Co., Inc sign licensing agreement for Tafluprost, treatment for glaucoma and ocular hypertension. 2009 Apr.
5. Santen Pharmaceutical. Merck & Co., Inc. and Santen sign licensing agreement in ophthalmology. 2009 Apr.
6. Pozarowska D. Safety and tolerability of tafluprost in treatment of elevated intraocular pressure in open-angle glaucoma and ocular hypertension. Clin Ophthalmol. 2010 Oct 21;4:1229-36.
7. Merck & Co. Merck’s investigational prostaglandin analogue ophthalmic medication Tafluprost meets primary endpoint in Phase III study. 2011 May.
8. Uusitalo RJ, Palkama A. Efficacy and safety of timolol/pilocarpine combination drops in glaucoma patients. Acta Ophthalmol (Copenh). 1994 Aug;72(4):496-504.
9. Proksofelin. Pharmbook. 2006. Available at: www.pharmabook.net/en/vegetotropnye-sredstva/adrenomimeti4eskie-sredstva/alfa-adrenomimetiki/proksofelin--glaznye-kapli-.html (accessed August 2011).
10. Ermakova VN, Malinina SL, Abdulkadyrova MZh, et al. Therapy of patients with primary open-angle glaucoma with proxofelin, a combined form of proxodolol. Vestn Oftalmol. 1999 Jan-Feb;115(1):3-5.
11. Clonidine. Drug Information Online. 2010 Nov. Available at: www.drugs.com/clonidine.html (accessed July 2011).
12. Hughes BA, Bacharach J, Craven ER, et al. A three-month, multicenter, double-masked study of the safety and efficacy of travoprost 0.004%/timolol 0.5% ophthalmic solution compared to travoprost 0.004% ophthalmic solution and timolol 0.5% dosed concomitantly in subjects with open angle glaucoma or ocular hypertension. J Glaucoma. 2005;14:392-9.
13. Rossi GC, Pasinetti GM, Bracchino M, et al. Switching from concomitant latanoprost 0.005% and timolol 0.5% to a fixed combination of travoprost 0.004%/timolol 0.5% in patients with primary open-angle glaucoma and ocular hypertension: a 6-month, multicenter, cohort study. Expert Opin Pharmacother. 2009 Aug;10(11):1705-11.
14. Young M. FDA approval of Xalcom eagerly anticipated. EyeWorld News Service. Available at: www.eyeworld.org/article.php?sid=2242&strict=0&morphologic=0&query= (accessed July 2011).
15. Lanzl I, Raber T. Efficacy and tolerability of the fixed combination of brinzolamide 1% and timolol 0.5% in daily practice. Clin Ophthalmol. 2011;5:291-8.