Eyeworld

EW NEWS & OPINION 26 November 2015 BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE TRAVATAN Z ® (travoprost ophthalmic solution) 0.004% is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. DOSAGE AND ADMINISTRATION The recommended dosage is one drop in the affected eye(s) once daily in the evening. TRAVATAN Z ® (travoprost ophthalmic solution) should not be administered more than once daily since it has been shown that more frequent administration of prostaglandin analogs may decrease the intraocular pressure lowering effect. Reduction of the intraocular pressure starts approximately 2 hours after the fi rst administration with maximum effect reached after 12 hours. TRAVATAN Z ® 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 fi ve (5) minutes apart. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Pigmentation Travoprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is expected to increase as long as travoprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of travoprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known. Iris color 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 TRAVATAN Z ® (travoprost ophthalmic solution) 0.004% can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. Eyelash Changes TRAVATAN Z ® Solution may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, thickness, and number of lashes. Eyelash changes are usually reversible upon discontinuation of treatment. Intraocular Infl ammation TRAVATAN Z ® Solution should be used with caution in patients with active intraocular infl ammation (e.g., uveitis) because the infl ammation may be exacerbated. Macular Edema Macular edema, including cystoid macular edema, has been reported during treatment with travoprost ophthalmic solution. TRAVATAN Z ® Solution should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular edema. Angle-closure, Infl ammatory or Neovascular Glaucoma TRAVATAN Z ® Solution has not been evaluated for the treatment of angle-closure, infl ammatory or neovascular glaucoma. Bacterial Keratitis 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. Use with Contact Lenses Contact lenses should be removed prior to instillation of TRAVATAN Z ® Solution and may be reinserted 15 minutes following its administration. ADVERSE REACTIONS Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not refl ect the rates observed in practice. The most common adverse reaction observed in controlled clinical studies with TRAVATAN ® (travoprost ophthalmic solution) 0.004% and TRAVATAN Z ® (travoprost ophthalmic solution) 0.004% was ocular hyperemia which was reported in 30 to 50% of patients. Up to 3% of patients discontinued therapy due to conjunctival hyperemia. Ocular adverse reactions reported at an incidence of 5 to 10% in these clinical studies included decreased visual acuity, eye discomfort, foreign body sensation, pain and pruritus. Ocular adverse reactions reported at an incidence of 1 to 4% in clinical studies with TRAVATAN ® or TRAVATAN Z ® Solutions included abnormal vision, blepharitis, blurred vision, cataract, conjunctivitis, corneal staining, dry eye, iris discoloration, keratitis, lid margin crusting, ocular infl ammation, photophobia, subconjunctival hemorrhage and tearing. Nonocular adverse reactions reported at an incidence of 1 to 5% in these clinical studies were allergy, angina pectoris, anxiety, arthritis, back pain, bradycardia, bronchitis, chest pain, cold/fl u syndrome, depression, dyspepsia, gastrointestinal disorder, headache, hypercholesterolemia, hypertension, hypotension, infection, pain, prostate disorder, sinusitis, urinary incontinence and urinary tract infections. In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid sulcus have been observed. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C Teratogenic effects: Travoprost was teratogenic in rats, at an intravenous (IV) dose up to 10 mcg/kg/day (250 times the maximal recommended human ocular dose (MRHOD), evidenced by an increase in the incidence of skeletal malformations as well as external and visceral malformations, such as fused sternebrae, domed head and hydrocephaly. Travoprost was not teratogenic in rats at IV doses up to 3 mcg/kg/day (75 times the MRHOD), or in mice at subcutaneous doses up to 1 mcg/kg/day (25 times the MRHOD). Travoprost produced an increase in post-implantation losses and a decrease in fetal viability in rats at IV doses > 3 mcg/kg/day (75 times the MRHOD) and in mice at subcutaneous doses > 0.3 mcg/kg/day (7.5 times the MRHOD). In the offspring of female rats that received travoprost subcutaneously from Day 7 of pregnancy to lactation Day 21 at doses of ≥ 0.12 mcg/kg/day (3 times the MRHOD), the incidence of postnatal mortality was increased, and neonatal body weight gain was decreased. Neonatal development was also affected, evidenced by delayed eye opening, pinna detachment and preputial separation, and by decreased motor activity. There are no adequate and well-controlled studies of TRAVATAN Z ® (travoprost ophthalmic solution) 0.004% administration in pregnant women. Because animal reproductive studies are not always predictive of human response, TRAVATAN Z ® Solution should be administered during pregnancy only if the potential benefi t justifi es the potential risk to the fetus. Nursing Mothers A study in lactating rats demonstrated that radiolabeled travoprost and/or its metabolites were excreted in milk. 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 TRAVATAN Z ® Solution is administered to a nursing woman. Pediatric Use Use in pediatric patients below the age of 16 years is not recommended because of potential safety concerns related to increased pigmentation following long-term chronic use. Geriatric Use No overall clinical differences in safety or effectiveness have been observed between elderly and other adult patients. Hepatic and Renal Impairment Travoprost ophthalmic solution 0.004% has been studied in patients with hepatic impairment and also in patients with renal impairment. No clinically relevant changes in hematology, blood chemistry, or urinalysis laboratory data were observed in these patients. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies in mice and rats at subcutaneous doses of 10, 30, or 100 mcg/kg/day did not show any evidence of carcinogenic potential. However, at 100 mcg/kg/day, male rats were only treated for 82 weeks, and the maximum tolerated dose (MTD) was not reached in the mouse study. The high dose (100 mcg/kg) corresponds to exposure levels over 400 times the human exposure at the maximum recommended human ocular dose (MRHOD) of 0.04 mcg/kg, based on plasma active drug levels. Travoprost was not mutagenic in the Ames test, mouse micronucleus test or rat chromosome aberration assay. A slight increase in the mutant frequency was observed in one of two mouse lymphoma assays in the presence of rat S-9 activation enzymes. Travoprost did not affect mating or fertility indices in male or female rats at subcutaneous doses up to 10 mcg/kg/day [250 times the maximum recommended human ocular dose of 0.04 mcg/kg/day on a mcg/kg basis (MRHOD)]. At 10 mcg/kg/day, the mean number of corpora lutea was reduced, and the post-implantation losses were increased. These effects were not observed at 3 mcg/kg/day (75 times the MRHOD). PATIENT COUNSELING INFORMATION Potential for Pigmentation 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 TRAVATAN Z ® (travoprost ophthalmic solution) 0.004%. Potential for Eyelash Changes Patients should also be informed of the possibility of eyelash and vellus hair changes in the treated eye during treatment with TRAVATAN Z ® Solution. 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. Handling the Container Patients should be instructed to avoid allowing the tip of the dispensing container to contact the eye, surrounding structures, fi ngers, or any other surface in order to avoid contamination of the solution by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. When to Seek Physician Advice Patients should also be advised that if they develop an intercurrent ocular condition (e.g., trauma or infection), have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid reactions, they should immediately seek their physician's advice concerning the continued use of TRAVATAN Z ® Solution. Use with Contact Lenses Contact lenses should be removed prior to instillation of TRAVATAN Z ® Solution and may be reinserted 15 minutes following its administration. Use with Other Ophthalmic Drugs If more than one topical ophthalmic drug is being used, the drugs should be administered at least fi ve (5) minutes between applications. Rx Only U.S. Patent Nos. 5,631,287; 5,889,052, 6,011,062; 6,235,781; 6,503,497; and 6,849,253 ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA © 2006, 2010, 2011, 2012 Novartis 4/15 TRV15086JAD 91166 EYEWORLD 11115 Vision problems continued from page 25 CTE mostly affects contact sports athletes (football, rugby, and soccer, among others). The main problem, however, is that CTE can only be diagnosed at autopsy. In recent years, clinicians have been closely monitoring concussion, the most common consequence of TBI in contact sports. But the neurolog- ical dysfunction that happens after concussion cannot be measured yet. Recommendations today are mostly centered on the resolution of acute symptoms such as headache, confu- sion, and sensitivity to light. Ann C. McKee, MD, professor of neurology and pathology, Boston University, reported at the 2015 As- sociation for Research in Vision and Ophthalmology (ARVO) meeting that: "retinal pathology is an early feature of CTE. Our preliminary studies demonstrate that abnormal aggregates are found in the retina of most individuals with CTE at post-mortem examination, includ- ing those with early stage disease." Still, it is debatable whether a single traumatic brain injury could cause CTE. Experts are working on neuro- imaging tools, cerebrospinal fluid and blood biomarkers that would, in the future, help detect TBI and accompanying visual problems early on. The retina is often an area of focus. For example, a group of re- searchers from Iowa investigated the effect of TBI on retinal ganglion cells (RGCs) and published their results in Investigative Ophthalmology & Visual Science in December 2014. "Efficient observation and anal- ysis of individual RGC physiology in vitro using multi-electrode recording of the intact retina revealed that the period of active RGC injury and dysfunction leading to chronic visual loss occurs much earlier than previously anticipated, approximate- ly 4 weeks following blast exposure," the researchers reported. "Provoc- ative PERG testing confirmed that RGCs are correspondingly more susceptible to disruption of normal physiology by stressful conditions, such as a transient, postural-induced rise in IOP during this latent period following blast injury." In other words, the researchers found that a multi-electrode ar- ray and pattern electroretinogram (PERG) test can serve as a noninva- sive test in living organisms capable of identifying early damage to the visual system, therefore reflecting corresponding damage in the brain. Also, the researchers tested whether a novel neuroprotective compound can be used as treatment in order to prevent in vivo func- tional deficits in the visual system. The neuroprotective agent (dubbed P7C3-S243) has been found effective in the protection of visual system dysfunction after TBI in mice mod- els. While results of this PERG test- ing are promising and may actually provide a basis in the development of diagnostic tests for patients at risk of developing CNS and visual system injuries after TBI, a lot of work still needs to be done before such a test can be available in the clinical setting. In the meantime, clinicians are closely relying on the symptoms correlated to CTE such as concus- sion, visual deterioration, behavioral

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