EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.
Issue link: https://digital.eyeworld.org/i/111385
48 EW REFRACTIVE SURGERY February 2013 Biomechanics continued from page 46 Figure 2 shows how this concept changes the way that we think about the safety of ReLEx SMILE compared with PRK and LASIK. In PRK, the excimer laser ablation removes Bowman���s layer and tissue from the (strongest) anterior stroma. In LASIK, the flap severs Bowman���s layer and the lamellae within the (strongest) anterior stroma (assuming that Bowman���s layer and the stromal component of the flap no longer contribute to corneal strength post-op) as has been shown previously.4 The excimer laser ablation then removes tissue from the anterior-most stroma under the flap, which is the strongest out of the remaining tissue. In comparison, stromal removal in ReLEx SMILE is limited only to the stroma that needs removing, similar to PRK, however the removal is being done within inert, weaker stroma in ReLEx SMILE leaving the strongest anterior stroma intact. LUMIGAN 0.01% AND 0.03% (bimatoprost ophthalmic solution) �� Brief Summary���Please see the LUMIGAN�� 0.01% and 0.03% package insert for full Prescribing Information. INDICATIONS AND USAGE LUMIGAN�� 0.01% and 0.03% (bimatoprost ophthalmic solution) is indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Pigmentation: Bimatoprost 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 bimatoprost 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 bimatoprost, 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 LUMIGAN�� 0.01% and 0.03% (bimatoprost ophthalmic solution) can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. Eyelash Changes: LUMIGAN�� 0.01% and 0.03% 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 Inflammation: LUMIGAN�� 0.01% and 0.03% should be used with caution in patients with active intraocular inflammation (e.g., uveitis) because the inflammation may be exacerbated. Macular Edema: Macular edema, including cystoid macular edema, has been reported during treatment with bimatoprost ophthalmic solution. LUMIGAN�� 0.01% and 0.03% 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, Inflammatory, or Neovascular Glaucoma: LUMIGAN�� 0.01% and 0.03% has not been evaluated for the treatment of angle-closure, inflammatory 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 LUMIGAN�� 0.01% and 0.03% 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 reflect the rates observed in practice. In clinical studies with bimatoprost ophthalmic solutions (0.01% or 0.03%) the most common adverse reaction was conjunctival hyperemia (range 25%���45%). Approximately 0.5% to 3% of patients discontinued therapy due to conjunctival hyperemia with 0.01% or 0.03% bimatoprost ophthalmic solutions. Other common reactions (>10%) included growth of eyelashes, and ocular pruritus. Additional ocular adverse reactions (reported in 1 to 10% of patients) with bimatoprost ophthalmic solutions included ocular dryness, visual disturbance, ocular burning, foreign body sensation, eye pain, pigmentation of the periocular skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, ocular irritation, eyelash darkening, eye discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, increases in iris pigmentation, conjunctival edema, conjunctival hemorrhage, and abnormal hair growth. Intraocular inflammation, reported as iritis, was reported in less than 1% of patients. Systemic adverse reactions reported in approximately 10% of patients with bimatoprost ophthalmic solutions were infections (primarily colds and upper respiratory tract infections). Other systemic adverse reactions (reported in 1 to 5% of patients) included headaches, abnormal liver function tests, and asthenia. Postmarketing Experience: The following reactions have been identified during postmarketing use of LUMIGAN�� 0.01% and 0.03% in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to LUMIGAN�� or , a combination of these factors, include: dizziness, eyelid edema, hypertension, nausea, and periorbital and lid changes associated with a deepening of the eyelid sulcus. Therefore, we can conclude that a cornea after ReLEx SMILE is not only stronger than the equivalent treatment as LASIK, but also stronger than the equivalent treatment as PRK. Taking this concept further, the post-op total tensile strength in LASIK will decrease with increasing flap thickness (obviously). However, this model demonstrates that the opposite is true for ReLEx SMILE: The thicker the cap and the deeper USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category C Teratogenic effects: In embryo/fetal developmental studies in pregnant mice and rats, abortion was observed at oral doses of bimatoprost which achieved at least 33 or 97 times, respectively, the maximum intended human exposure based on blood AUC levels. At doses at least 41 times the maximum intended human exposure based on blood AUC levels, the gestation length was reduced in the dams, the incidence of dead fetuses, late resorptions, peri- and postnatal pup mortality was increased, and pup body weights were reduced. There are no adequate and well-controlled studies of LUMIGAN�� 0.01% and 0.03% (bimatoprost ophthalmic solution) administration in pregnant women. Because animal reproductive studies are not always predictive of human response LUMIGAN�� should be administered during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether LUMIGAN�� 0.01% and 0.03% is excreted in human milk, although in animal studies, bimatoprost has been shown to be excreted in breast milk. Because many drugs are excreted in human milk, caution should be exercised when LUMIGAN�� 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 Impairment: In patients with a history of liver disease or abnormal ALT, AST and/or bilirubin at baseline, bimatoprost 0.03% had no adverse effect on liver function over 48 months. OVERDOSAGE No information is available on overdosage in humans. If overdose with LUMIGAN�� 0.01% and 0.03% (bimatoprost ophthalmic solution) occurs, treatment should be symptomatic. In oral (by gavage) mouse and rat studies, doses up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 70 times higher than the accidental dose of one bottle of LUMIGAN�� 0.03% for a 10 kg child. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Bimatoprost was not carcinogenic in either mice or rats when administered by oral gavage at doses of up to 2 mg/kg/day and 1 mg/kg/day respectively (at least 192 and 291 times the recommended human exposure based on blood AUC levels respectively) for 104 weeks. Bimatoprost was not mutagenic or clastogenic in the Ames test, in the mouse lymphoma test, or in the in vivo mouse micronucleus tests. Bimatoprost did not impair fertility in male or female rats up to doses of 0.6 mg/kg/day (at least 103 times the recommended human exposure based on blood AUC levels). 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 LUMIGAN�� 0.01% and 0.03% (bimatoprost ophthalmic solution). 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 LUMIGAN�� 0.01% and 0.03%. 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, fingers, 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 LUMIGAN�� 0.01% and 0.03%. Use with Contact Lenses: Patients should be advised that LUMIGAN�� 0.01% and 0.03% contains benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of LUMIGAN�� and may be reinserted 15 minutes following its administration. Use with Other Ophthalmic Drugs: Patients should be advised that if more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes between applications. �� 2012 Allergan, Inc., Irvine, CA 92612 marks owned by Allergan, Inc Patented. See: www.allergan.com/products/patent_notices Made in the U.S.A. Rx only APC70EN12 based on 71807US13. �� the lenticular tissue removal, the more residual tensile strength remains. This finding is logical from the knowledge that anterior stroma is stronger and supports the notion that it should be possible to correct much higher levels of myopia by ReLEx SMILE compared to LASIK or PRK. The conclusion that ���deeper is better��� also brings the added advantage of potentially further reducing the impact of ReLEx SMILE on dry eye as even more of the anterior corneal anatomy is preserved, hence further reducing the disruption of the anterior stromal nerve plexus. In summary, by making the paradigm shift away from classical residual stromal thickness limits to thinking about post-op total tensile strength, it starts to become clear that ReLEx SMILE is biomechanically stronger than not only LASIK but also PRK. The flapless intrastromal ReLEx SMILE procedure brings the advantage of leaving the strongest anterior stromal lamellae intact to maximize the strength of the cornea after the procedure. The idea that ���deeper is better��� opens the door to the possibility of correcting significantly higher levels of myopia with corneal laser refractive surgery than previously possible with LASIK or PRK. EW References 1. Sekundo W, Kunert KS, Blum M. Small incision corneal refractive surgery using the small incision lenticule extraction (SMILE) procedure for the correction of myopia and myopic astigmatism: results of a 6 month prospective study. Br J Ophthalmol. 2011;95:335-339. 2. Shah R, Shah S, Sengupta S. Results of small incision lenticule extraction: All-inone femtosecond laser refractive surgery. J Cataract Refract Surg. 2011;37:127-137. 3. Randleman JB, Dawson DG, Grossniklaus HE, McCarey BE, Edelhauser HF. Depth-dependent cohesive tensile strength in human donor corneas: implications for refractive surgery. J Refract Surg. 2008;24:S85-89. 4. Schmack I, Dawson DG, McCarey BE, Waring GO 3rd, Grossniklaus HE, Edelhauser HF. Cohesive tensile strength of human LASIK wounds with histologic, ultrastructural, and clinical correlations. J Refract Surg. 2005 Sep-Oct; 21:5:433-45. Editors��� note: Dr. Reinstein practices at the London Vision Clinic, London, and is affiliated with the Department of Ophthalmology, Columbia University Medical College, New York, and the Centre Hospitalier National d���Ophtalmologie, Paris. He has financial interests with Carl Zeiss Meditec and ArcScan Inc. (Morrison, Colo.). Contact information Reinstein: +44 207 224 1005,�� dzr@londonvisionclinic.com