Long-Term Intraocular Pressure-Lowering Effects and Adverse Events of Ripasudil in Patients with Glaucoma or Ocular Hypertension over 24 Months.

INTRODUCTION: Glaucoma is a leading cause of irreversible blindness and ripasudil was the first Rho kinase inhibitor approved as antiglaucoma medication. Here we present the final analysis of the ROCK-J study, a large-scale post-marketing surveillance study to evaluate the long-term safety and effectiveness of ripasudil in Japanese patients with glaucoma or ocular hypertension in a real-word clinical setting. METHODS: ROCK-J was a 24-month, prospective, open-label, observational study that included ripasudil-naïve patients with glaucoma or ocular hypertension who were initiating treatment with ripasudil according to the Japanese approved indication between June 1, 2015 and April 30, 2017. The primary safety endpoint was the incidence of adverse drug reactions (ADRs) (including blepharitis, plus assessment of its background factors); the primary efficacy endpoint was change in intraocular pressure (IOP) from baseline to 24 months. RESULTS: A total of 3374 Japanese patients with glaucoma or ocular hypertension were evaluated for safety and 3178 for effectiveness of ripasudil over a mean 524.5-day observational period. Overall, 853 (25.3%) patients experienced adverse drug reactions; the most common were blepharitis (8.6%), conjunctival hyperemia (8.5%), and conjunctivitis (6.3%). Multivariate analyses demonstrated that patients were more likely to experience the ADR blepharitis with ripasudil treatment if they were female (hazard ratio [HR] 1.307; p = 0.040), had comorbid or a previous history of blepharitis (HR 2.178; p = 0.001), or had a history of allergy to pollen (HR 1.645; p = 0.003) or medication (HR 2.276; p < 0.001). IOP decreased significantly from baseline with ripasudil; the least-squares mean ± standard error change in IOP from baseline to 24 months was - 2.6 ± 0.1 mmHg (p < 0.001). Significant IOP changes were seen in four types of glaucoma, namely primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, and secondary glaucoma, and ocular hypertension. CONCLUSION: Ripasudil was safe and effective as an antiglaucoma medication with no new safety signals identified and significant reductions in IOP maintained over 24 months of treatment.

Safety of topical ophthalmic antibiotics in pregnant women with hordeola, chalazia, blepharitis, or bacterial conjunctivitis: propensity score analyses.

OBJECTIVE: To investigate the association between exposure to topical ophthalmic antibiotics during pregnancy and adverse neonatal outcomes. METHODS: In this retrospective cohort study, we identified pregnant women with hordeola, chalazia, blepharitis, or bacterial conjunctivitis from 2005 to 2018 using the Japanese Medical Data Centre Claims Database. From the eligible women, we extracted women who were dispensed no topical antibiotics during the first trimester (non-antibiotic group), women who were dispensed topical fluoroquinolones alone at least once (fluoroquinolone alone group), and women who were dispensed any single type of antibiotic (single-antibiotic group). We compared the frequency of congenital anomalies (CA), preterm birth (PB), low birth weight (LBW), and the composite outcome of these three between the fluoroquinolone and non-antibiotic groups and between the single-antibiotic and non-antibiotic groups, using propensity score adjustment. RESULTS: A total of 891 eligible women were identified. In the fluoroquinolone (n = 409) and non-antibiotic (n = 309) groups, CA occurred in 6.8% and 6.8%, PB in 2.4% and 3.2%, LBW in 2.9% and 3.2%, and the composite outcome in 10.5% and 11.3%, respectively. Analysis using propensity score adjustment showed no significant difference between the groups in the frequency of CA (adjusted odds ratio, 1.15; 95% confidence interval, 0.61-2.18), PB (0.80; 0.30-2.17), LBW (1.08; 0.45-2.63), or the composite outcome (1.12; 0.67-1.87). Comparison of the single-antibiotic and non-antibiotic groups showed similar results. CONCLUSIONS: Topical ophthalmic antibiotics for hordeola, chalazia, blepharitis, or bacterial conjunctivitis during the first trimester were not associated with increased adverse neonatal outcomes.

Retrospective analysis of adverse events with dupilumab reported to the United States Food and Drug Administration.

BACKGROUND: Atopic dermatitis (AD) is one of the most common inflammatory skin diseases and has aesthetic, physical, and emotional-social sequelae when left untreated. OBJECTIVE: To classify the most common adverse reactions associated with dupilumab treatment in patients with AD. METHODS: The United States Food and Drug Administration Adverse Event Reporting (FAERS) database was analyzed for common adverse reactions associated with dupilumab, topical pimecrolimus, and topical tacrolimus. Phase III clinical trial data were used to compare the rate of herpes infections between the treatment group and placebo group. RESULTS: The most common adverse reaction associated with dupilumab was ocular complications. Herpes infections were extremely rare in the patients with AD being treated with dupilumab. LIMITATIONS: Prescribing information for dupilumab, topical pimecrolimus, and topical tacrolimus is not available. Adverse effects are reported by patients, health care providers, and pharmaceutical companies, they have not been corroborated. CONCLUSIONS: Ocular complications are the most common complication associated with dupilumab. The rate of herpes infection is low in patients being treated with dupilumab, topical pimecrolimus, and topical tacrolimus. There is no significant difference for the rate of herpes infection between, placebo, dupilumab, topical pimecrolimus, and the topical tacrolimus treatment group, suggesting that dupilumab does not affect herpes infection rates.

Real-world evidence of dupilumab efficacy and risk of adverse events: A systematic review and meta-analysis.

BACKGROUND: Dupilumab, the first biological drug to be approved for the treatment of moderate to severe atopic dermatitis in adolescents and adults, has shown good efficacy and safety in clinical trials. OBJECTIVE: To evaluate real-world data on the efficacy and safety of dupilumab in atopic dermatitis. METHODS: PubMed and EMBASE were searched for observational studies with data on efficacy, drug survival, and safety of dupilumab for the treatment of atopic dermatitis. Primary outcomes were mean percentage change in Eczema Area and Severity Index (EASI) score and proportion of atopic dermatitis patients achieving 50%, 75%, and 90% improvement in EASI score after dupilumab therapy. RESULTS: Twenty-two unique studies encompassing 3303 atopic dermatitis patients were included. After 16 weeks of dupilumab therapy, the pooled proportion of patients achieving 50%, 75%, and 90% EASI score improvement was 85.1%, 59.8%, and 26.8%, respectively, and the weighted mean reduction in EASI score was 69.6%. Conjunctivitis was the most common adverse event, reported in a pooled proportion of 26.1%. LIMITATIONS: Limited data in terms of size and follow-up time were available. CONCLUSION: Real-world data show that dupilumab is a successful and well-tolerated therapy for atopic dermatitis, but ocular adverse events commonly occur. Registries are needed to monitor for adverse events.

Dupilumab shows long-term effectiveness in a large cohort of treatment-refractory atopic dermatitis patients in daily practice: 52-Week results from the Dutch BioDay registry.

BACKGROUND: Real-life data on long-term effectiveness and safety of dupilumab in atopic dermatitis patients are limited. OBJECTIVE: To study 52-week effectiveness and safety of dupilumab in a prospective multicenter cohort of adult patients with treatment-refractory atopic dermatitis. METHODS: Patients treated with dupilumab and participating in the Dutch BioDay registry were included. Clinical effectiveness and safety were evaluated. RESULTS: Two hundred ten atopic dermatitis patients were included. Mean percentage change in Eczema Area and Severity Index score after 16 weeks was -70.0% (standard deviation 33.2%) and further decreased to -76.6% (standard deviation 30.6%) by week 52. A greater than or equal to 75% improvement in the score was achieved by 59.9% of individuals by week 16 and by 70.3% by week 52. The most reported adverse effect was conjunctivitis (34%). Limited patients (17; 8.1%) discontinued dupilumab treatment. LIMITATIONS: Because of the lack of a control group and observational design, factors of bias may have been induced. CONCLUSION: Treatment with dupilumab resulted in a rapid improvement in clinical outcome measures, and effectiveness further improved during the 52-week follow-up period.

Safety and Efficacy of Long-Term Ripasudil 0.4% Instillation for the Reduction of Intraocular Pressure in Japanese Open-Angle Glaucoma Patients.

Purpose: Rho-associated kinase-inhibitor ripasudil 0.4% eye drops are reportedly effective for the reduction of intraocular pressure (IOP) in glaucoma patients. However, the previous studies investigated the efficacy of IOP reduction for only about 1 year. Here, we evaluated the safety and efficacy of long-term ripasudil instillation in Japanese open-angle glaucoma (OAG) patients. Methods: This study involved 312 eyes of 312 Japanese OAG patients newly initiated with ripasudil treatment at Kyoto Prefectural University of Medicine and Oike-Ikeda Eye Clinic, Kyoto, Japan. In all patients, adverse events leading to discontinuation of ripasudil treatment were investigated. Of the 312 patients, 129 patients able to continue ripasudil administration for over 12-months post-treatment initiation were enrolled to investigate the long-term efficacy. IOP data at 0-, 1-, 3-, 6-, 12-, 18-, and 24-months post initiation of continuous ripasudil use were obtained, and the IOP values at each time point were then compared. The first period (from 1-6 months) and second period (from 12-24 months) IOP data were also compared based on the mixed model. Results: IOP at each time-point post-treatment initiation was significantly reduced compared with that at pre initiation (P < 0.05). Differences in IOP between the first and second periods of the study were not statistically significant (P = 0.058). Adverse events leading to discontinuation of treatment included blepharitis (15.7%) and conjunctival hyperemia (9.0%). Conclusions: We found that in Japanese OAG patients, 24-month ripasudil eye drop instillation is both safe and effective for lowering IOP and that blepharitis is the primary adverse event for discontinuation of use.

Corneal sterile infiltration induced by topical use of ocular hypotensive agent.

PURPOSE: To report two cases with corneal sterile infiltration presumably due to topical ocular hypotensive agent. METHOD: Case report. RESULTS: Case 1: A 65-year-old man presented with corneal opacity and neovascularization in his left eye. A diagnosis of glaucoma was made 2 years previously, and anti-glaucoma agents were prescribed (brimonidine tartrate, ripasudil hydrochloride hydrate, and brinzolamide) for both eyes. Case 2: A 75-year-old woman noticed corneal opacity in the left eye. A diagnosis of glaucoma was made 35 years previously, and anti-glaucoma agents were prescribed (brimonidine tartrate, 1% dorzolamide, and bimatoprost) for both eyes. In both cases, ocular examination revealed follicular conjunctivitis and blepharitis in both eyes, and corneal sterile infiltration with neovascularization in the left eyes. The three topical drugs were discontinued and replaced with 0.1% fluorometholone. Both the blepharitis and corneal sterile infiltration improved thereafter, although corneal opacity remained across the stromal layer. CONCLUSION: We encountered two cases of corneal and conjunctival complications that were suspected as side effects after brimonidine eye drop use. Special care should be taken to observe the condition of ocular surface when topical brimonidine is administered.

Management and outcomes of proteasome inhibitor associated chalazia and blepharitis: a case series.

BACKGROUND: The purpose of this case series was to further characterize proteasome inhibitor associated chalazia and blepharitis, to investigate outcomes of different management strategies, and to propose a treatment algorithm for eyelid complications in this patient population. METHODS: This retrospective case series included sixteen patients found to have chalazia and/or blepharitis while receiving proteasome inhibitors for plasma cell disorders at Mount Sinai Hospital in New York, NY from January 2010 through January 2017. Main outcomes were complete resolution of eyelid complications and time to resolution. Student's t-test was used to compare average values and Fisher's exact test was used to compare proportions. RESULTS: Fourteen patients had chalazia and 10 had blepharitis. Chalazia averaged 5.4 mm, and 11 patients with chalazia experienced two or more lesions. Median follow-up time was 17 months. Average time from bortezomib exposure to onset of first eyelid complication was 3.4 months. Chalazia episodes were more likely to completely resolve than blepharitis episodes (p = 0.03). Ocular therapy alone was trialed for an average of 1.8 months before proceeding to bortezomib omission. Average time to eyelid complication resolution using ocular therapy alone was 1.8 months versus 3.1 months after bortezomib omission. In this series, the combination of ocular therapy and bortezomib omission led to complete resolution of eyelid complications more often than ocular therapy alone. CONCLUSION: Proteasome inhibitor associated eyelid complications were identified in sixteen patients with plasma cell disorders. Eyelid complications may be treated with a 2-month trial of conservative ocular therapies alone, followed by continuation of ocular therapy in combination with bortezomib omission if eyelid signs persist.

Long-term Side Effects Including Blepharitis Leading to Discontinuation of Ripasudil.

PRECIS: Blepharitis was the most common side effect leading to discontinuation of ripasudil therapy. Prior allergic reactions to other topical glaucoma were found to be a risk factor for ripasudil-induced blepharitis. PURPOSE: To report the incidence proportion of blepharitis and its relating factors due to long-term use of 0.4% riapasudil, a Rho-kinase inhibitor, in glaucoma patients of a clinical setting. PATIENTS AND METHODS: One hundred three eyes of 103 consecutive glaucoma patients who started ripasudil treatment between December 2014 and February 2017 at our institute, and who had a follow-up period of over 6 months were enrolled in this study. Incidence proportion, time required for recovery and risk factors associated with blepharitis and other side effects that led to discontinuation of ripasudil treatment were considered. RESULTS: The most frequently observed side effect was blepharitis (25.2%). The 12- and 24-month discontinuation rate due to blepharitis was 21.1%±8.2% and 34.6%±11.8% (average±SE), respectively (Kaplan-Meier analysis). Most patients recovered from blepharitis symptoms within 4 weeks, but 5 patients required over 8 weeks for recovery. Past history of allergic reactions to other topical glaucoma medication was significantly correlated with the manifestation of blepharitis (Cox proportional hazard model, P<0.007) while age, sex, intraocular pressure reduction rate, number of administered eye drops, history of systemic allergic diseases were not. CONCLUSIONS: Blepharitis was the most common reason for discontinuation of ripasudil treatment. Although most cases were resolved spontaneously, prolonged blepharitis was observed in a few patients. A past history of allergic reaction to other glaucoma medication indicates a higher possibility of blepharitis with ripasudil use and warrants careful administration.