OSLI Retina

December 2016

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For complete details, see Full Prescribing Information. 1 INDICATIONS AND USAGE EYLEA ® (aflibercept) Injection is indicated for the treatment of patients with Neovascular (Wet) Age-Related Macular Degeneration (AMD), Macular Edema following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), and Diabetic Retinopathy (DR) in Patients with DME. 2 DOSAGE AND ADMINISTRATION 2.1 Important Injection Instructions. For ophthalmic intravitreal injection. EYLEA must only be administered by a qualified physician. 2.2 Neovascular (Wet) Age-Related Macular Degeneration (AMD). The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 12 weeks (3 months), followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks. 2.3 Macular Edema Following Retinal Vein Occlusion (RVO). The recommended dose for EYLEA is (0.05 mL or 50 microliters) administered by intravitreal injection once every 4 weeks (monthly). 2.4 Diabetic Macular Edema (DME). The recommended dose for EYLEA is (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 5 injections followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks. 2.5 Diabetic Retinopathy (DR) in Patients with DME. The recommended dose for EYLEA is 2 mg (0.05 mL or 50 microliters) administered by intravitreal injection every 4 weeks (monthly) for the first 5 injections, followed by 2 mg (0.05 mL) via intravitreal injection once every 8 weeks (2 months). Although EYLEA may be dosed as frequently as 2 mg every 4 weeks (monthly), additional efficacy was not demonstrated when EYLEA was dosed every 4 weeks compared to every 8 weeks. 2.6 Preparation for Administration. EYLEA should be inspected visually prior to administration. If particulates, cloudiness, or discoloration are visible, the vial must not be used. Using aseptic technique, the intravitreal injection should be performed with a 30-gauge x ½-inch injection needle. For complete preparation for administration instructions, see full prescribing information. 2.7 Injection Procedure. The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include surgical hand disinfection and the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a topical broad–spectrum microbicide should be given prior to the injection. Immediately following the intravitreal injection, patients should be monitored for elevation in intraocular pressure. Appropriate monitoring may consist of a check for perfusion of the optic nerve head or tonometry. If required, a sterile paracentesis needle should be available. Following intravitreal injection, patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay (see Patient Counseling Information). Each vial should only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new vial should be used and the sterile field, syringe, gloves, drapes, eyelid speculum, filter, and injection needles should be changed before EYLEA is administered to the other eye. After injection, any unused product must be discarded. 3 DOSAGE FORMS AND STRENGTHS Single-use, glass vial designed to provide 0.05 mL of 40 mg/mL solution (2 mg) for intravitreal injection. 4 CONTRAINDICATIONS EYLEA is contraindicated in patients with • Ocular or periocular infections • Active intraocular inflammation • Known hypersensitivity to aflibercept or any of the excipients in EYLEA. Hypersensitivity reactions may manifest as severe intraocular inflammation 5 WARNINGS AND PRECAUTIONS 5.1 Endophthalmitis and Retinal Detachments. Intravitreal injections, including those with EYLEA, have been associated with endophthalmitis and retinal detachments (see Adverse Reactions). Proper aseptic injection technique must always be used when administering EYLEA. Patients should be instructed to report any symptoms suggestive of endophthalmitis or retinal detachment without delay and should be managed appropriately (see Dosage and Administration and Patient Counseling Information). 5.2 Increase in Intraocular Pressure. Acute increases in intraocular pressure have been seen within 60 minutes of intravitreal injection, including with EYLEA (see Adverse Reactions). Sustained increases in intraocular pressure have also been reported after repeated intravitreal dosing with vascular edothelial growth factor (VEGF) inhibitors. Intraocular pressure and the perfusion of the optic nerve head should be monitored and managed appropriately (see Dosage and Administration). 5.3 Thromboembolic Events. There is a potential risk of arterial thromboembolic events (ATEs) following intravitreal use of VEGF inhibitors, including EYLEA. ATEs are defined as nonfatal stroke, nonfatal myocardial infarction, or vascular death (including deaths of unknown cause). The incidence of reported thromboembolic events in wet AMD studies during the first year was 1.8% (32 out of 1824) in the combined group of patients treated with EYLEA. The incidence in the DME studies from baseline to week 52 was 3.3% (19 out of 578) in the combined group of patients treated with EYLEA compared with 2.8% (8 out of 287) in the control group; from baseline to week 100, the incidence was 6.4% (37 out of 578) in the combined group of patients treated with EYLEA compared with 4.2% (12 out of 287) in the control group. There were no reported thromboembolic events in the patients treated with EYLEA in the first six months of the RVO studies. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section of the labeling: • Endophthalmitis and retinal detachments • Increased intraocular pressure • Thromboembolic events 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials of the same or another drug and may not reflect the rates observed in practice. A total of 2711 patients treated with EYLEA constituted the safety population in seven phase 3 studies. Among those, 2110 patients were treated with the recommended dose of 2 mg. Serious adverse reactions related to the injection procedure have occurred in <0.1% of intravitreal injections with EYLEA including endophthalmitis and retinal detachment. The most common adverse reactions (≥5%) reported in patients receiving EYLEA were conjunctival hemorrhage, eye pain, cataract, vitreous floaters, intraocular pressure increased, and vitreous detachment. Neovascular (Wet) Age-Related Macular Degeneration (AMD). The data described below reflect exposure to EYLEA in 1824 patients with wet AMD, including 1223 patients treated with the 2-mg dose, in 2 double- masked, active-controlled clinical studies (VIEW1 and VIEW2) for 12 months. Table 1: Most Common Adverse Reactions (≥1%) in Wet AMD Studies Adverse Reactions EYLEA (N=1824) Active Control (ranibizumab) (N=595) Conjunctival hemorrhage 25% 28% Eye pain 9% 9% Cataract 7% 7% Vitreous detachment 6% 6% Vitreous floaters 6% 7% Intraocular pressure increased 5% 7% Ocular hyperemia 4% 8% Corneal epithelium defect 4% 5% Detachment of the retinal pigment epithelium 3% 3% Injection site pain 3% 3% Foreign body sensation in eyes 3% 4% Lacrimation increased 3% 1% Vision blurred 2% 2% Intraocular inflammation 2% 3% Retinal pigment epithelium tear 2% 1% Injection site hemorrhage 1% 2% Eyelid edema 1% 2% Corneal edema 1% 1% Less common serious adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, and endophthalmitis. Macular Edema Following Retinal Vein Occlusion (RVO). The data described below reflect 6 months exposure to EYLEA with a monthly 2 mg dose in 218 patients following CRVO in 2 clinical studies (COPERNICUS and GALILEO) and 91 patients following BRVO in one clinical study (VIBRANT). Table 2: Most Common Adverse Reactions (≥1%) in RVO Studies Adverse Reactions CRVO BRVO EYLEA (N=218) Control (N=142) EYLEA (N=91) Control (N=92) Eye pain 13% 5% 4% 5% Conjunctival hemorrhage 12% 11% 20% 4% Intraocular pressure increased 8% 6% 2% 0% Corneal epithelium defect 5% 4% 2% 0% Vitreous floaters 5% 1% 1% 0% Ocular hyperemia 5% 3% 2% 2% Foreign body sensation in eyes 3% 5% 3% 0% Vitreous detachment 3% 4% 2% 0% Lacrimation increased 3% 4% 3% 0% Injection site pain 3% 1% 1% 0% Vision blurred 1% <1% 1% 1% Intraocular inflammation 1% 1% 0% 0% Cataract <1% 1% 5% 0% Eyelid edema <1% 1% 1% 0% Less common adverse reactions reported in <1% of the patients treated with EYLEA in the CRVO studies were corneal edema, retinal tear, hypersensitivity, and endophthalmitis. Diabetic Macular Edema (DME). The data described below reflect exposure to EYLEA in 578 patients with DME treated with the 2-mg dose in 2 double-masked, controlled clinical studies (VIVID and VISTA) from baseline to week 52 and from baseline to week 100. Table 3: Most Common Adverse Reactions (≥1%) in DME Studies Adverse Reactions Baseline to Week 52 Baseline to Week 100 EYLEA (N=578) Control (N=287) EYLEA (N=578) Control (N=287) Conjunctival hemorrhage 28% 17% 31% 21% Eye pain 9% 6% 11% 9% Cataract 8% 9% 19% 17% Vitreous floaters 6% 3% 8% 6% Corneal epithelium defect 5% 3% 7% 5% Intraocular pressure increased 5% 3% 9% 5% Ocular hyperemia 5% 6% 5% 6% Vitreous detachment 3% 3% 8% 6% Foreign body sensation in eyes 3% 3% 3% 3% Lacrimation increased 3% 2% 4% 2% Vision blurred 2% 2% 3% 4% Intraocular inflammation 2% <1% 3% 1% Injection site pain 2% <1% 2% <1% Eyelid edema <1% 1% 2% 1% Less common adverse reactions reported in <1% of the patients treated with EYLEA were hypersensitivity, retinal detachment, retinal tear, corneal edema, and injection site hemorrhage. 6.2 Immunogenicity. As with all therapeutic proteins, there is a potential for an immune response in patients treated with EYLEA. The immunogenicity of EYLEA was evaluated in serum samples. The immunogenicity data reflect the percentage of patients whose test results were considered positive for antibodies to EYLEA in immunoassays. The detection of an immune response is highly dependent on the sensitivity and specificity of the assays used, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to EYLEA with the incidence of antibodies to other products may be misleading. In the wet AMD, RVO, and DME studies, the pre-treatment incidence of immunoreactivity to EYLEA was approximately 1% to 3% across treatment groups. After dosing with EYLEA for 24-100 weeks, antibodies to EYLEA were detected in a similar percentage range of patients. There were no differences in efficacy or safety between patients with or without immunoreactivity. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy. Pregnancy Category C. Aflibercept produced embryo- fetal toxicity when administered every three days during organogenesis to pregnant rabbits at intravenous doses ≥3 mg per kg, or every six days at subcutaneous doses ≥0.1 mg per kg. Adverse embryo-fetal effects included increased incidences of postimplantation loss and fetal malformations, including anasarca, umbilical hernia, diaphragmatic hernia, gastroschisis, cleft palate, ectrodactyly, intestinal atresia, spina bifida, encephalomeningocele, heart and major vessel defects, and skeletal malformations (fused vertebrae, sternebrae, and ribs; supernumerary vertebral arches and ribs; and incomplete ossification). The maternal No Observed Adverse Effect Level (NOAEL) in these studies was 3 mg per kg. Aflibercept produced fetal malformations at all doses assessed in rabbits and the fetal NOAEL was less than 0.1 mg per kg. Administration of the lowest dose assessed in rabbits (0.1 mg per kg) resulted in systemic exposure (AUC) that was approximately 10 times the systemic exposure observed in humans after an intravitreal dose of 2 mg. There are no adequate and well-controlled studies in pregnant women. EYLEA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers. It is unknown whether aflibercept is excreted in human milk. Because many drugs are excreted in human milk, a risk to the breastfed child cannot be excluded. EYLEA is not recommended during breastfeeding. A decision must be made whether to discontinue nursing or to discontinue treatment with EYLEA, taking into account the importance of the drug to the mother. 8.4 Pediatric Use. The safety and effectiveness of EYLEA in pediatric patients have not been established. 8.5 Geriatric Use. In the clinical studies, approximately 76% (2049/2701) of patients randomized to treatment with EYLEA were ≥65 years of age and approximately 46% (1250/2701) were ≥75 years of age. No significant differences in efficacy or safety were seen with increasing age in these studies. 17 PATIENT COUNSELING INFORMATION In the days following EYLEA administration, patients are at risk of developing endophthalmitis or retinal detachment. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patients to seek immediate care from an ophthalmologist (see Warnings and Precautions). Patients may experience temporary visual disturbances after an intravitreal injection with EYLEA and the associated eye examinations (see Adverse Reactions). Advise patients not to drive or use machinery until visual function has recovered sufficiently. BRIEF SUMMARY OF FULL PRESCRIBING INFORMATION Manufactured by: Regeneron Pharmaceuticals, Inc. 777 Old Saw Mill River Road Tarrytown, NY 10591-6707 U.S. License Number 1760 EYLEA is a registered trademark of Regeneron Pharmaceuticals, Inc. © 2015, Regeneron Pharmaceuticals, Inc. All rights reserved. Issue Date: March 2015 Initial U.S. Approval: 2011 Regeneron U.S. Patents 7,070,959; 7,303,746; 7,303,747; 7,306,799; 7,374,757; 7,374,758; 7,531,173; 7,608,261; 7,972,598; 8,029,791; 8,092,803; 8,647,842; and other pending patents. LEA-0721

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