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Olumiant ® ▼ (baricitinib)
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Olumiant Summary of Product Characteristics (SmPC)
Olumiant® ▼ (baricitinib): Incidence of Ocular Events in the Atopic Dermatitis Clinical Trials
In the atopic dermatitis clinical trials, 114 (4.5%) adverse events of eye disorders were reported by patients treated with baricitinib; 5 (0.2%) adverse events were reported as serious events.
Risk of Ocular Events in Patients With Atopic Dermatitis
In large-scale epidemiologic studies, the prevalence of ocular comorbidities were noted to be higher in the AD population compared to the general population, in a severity-dependent manner.1,2 Chronic rubbing and scratching around the eyes due to uncontrolled AD and ocular inflammation even in the absence of visible skin symptoms, may contribute to the risk of developing an ocular comorbidity.3
The etiology of specific ocular events in the context of AD is complex and several factors are thought to contribute to the complexity including
dysregulation of the intrinsic immune system
physical trauma from eye rubbing
side effects from AD medications, and
genetics.2
Patients with AD have an increased risk of conjunctivitis and atopic keratoconjunctivitis. Other ocular diseases associated with AD include eyelid dermatitis, keratoconjunctivitis, keratoconus, cataract, and retinal detachment. Patients with AD are also at higher risk for bacterial and viral ocular infections.3
Ocular Events in the BREEZE-AD Clinical Development Program
Clinical Trial Exclusion Criteria
In the BARI AD clinical trial program, there were no specific exclusion criteria regarding ocular events. Patients were excluded from enrollment if they had a current or recent clinically serious viral, bacterial, fungal, parasitic infection, or any other infection within 4 weeks of randomization that, in the opinion of the investigator, would pose an unacceptable risk to the patient if participating in the study.4
Treatment-Emergent Eye Disorders in the Atopic Dermatitis Clinical Trials
Table 3 describes integrated data sets used to evaluate safety in the AD clinical trials.
Table 1 summarizes the incidence of ocular events by PT within the eye disorders SOC in the BARI AD clinical trial program.
Table 1. Treatment-Emergent Adverse Events Within the Eye Disorders System Organ Class4
|
|
|
|
|
|
|
|
|
|
|
|
|
BARI
2 mg Placebo-Controlleda |
BARI
4 mg Placebo-Controlleda |
BARI
2 mg vs 4 mga |
BARI
2 mg vs 4 mg ext |
All
BARI AD |
||||
|
|
Placebo |
BARI
2 mg |
Placebo |
BARI
4 mg |
BARI
2 mg |
BARI
4 mg |
BARI
2 mg |
BARI
4 mg |
All
Doses |
|
Eye disorders SOC |
21 (2.8) |
13 (1.7) |
18 (2.5) |
15 (2.6) |
12 (1.6) |
15 (2.6) |
23 (2.9) [5.1] |
33 (5.9) [7.7]c |
114 (4.5) [5.1] |
|
Conjunctivitis allergic |
8 (1.0) |
4 (0.6) |
7 (0.9) |
1 (0.2) |
4 (0.6) |
1 (0.2) |
7 (1.0) [1.5] |
7 (1.2) [1.4] |
34 (1.3) [1.5] |
|
Cataract |
0 |
2 (0.3) |
0 |
3 (0.4) |
2 (0.3) |
3 (0.4) |
2 (0.3) [0.5] |
4 (0.6) [0.9] |
12 (0.5) [0.5] |
|
Blepharitis |
1 (0.2) |
1 (0.1) |
1 (0.2) |
0 |
1 (0.1) |
0 |
4 (0.4) [0.8] |
3 (0.6) [0.6] |
10 (0.4) [0.4] |
|
Eye pruritus |
0 |
3 (0.3) |
0 |
2 (0.3) |
3 (0.3) |
2 (0.3) |
3 (0.3) [0.5] |
3 (0.5) [0.9] |
10 (0.4) [0.4] |
|
Chalazion |
0 |
1 (0.1) |
NR |
NR |
NR |
NR |
0 |
2 (0.4) [0.4] |
6 (0.2) [0.3] |
|
Vision blurred |
1 (0.1) |
0 |
1 (0.1) |
2 (0.4) |
0 |
2 (0.4) |
0 |
2 (0.4) [0.5] |
5 (0.2) [0.2] |
|
Conjunctival hemorrhage |
2 (0.3) |
0 |
2 (0.3) |
0 |
0 |
0 |
0 |
0 |
4 (0.2) [0.2] |
|
Conjunctival hyperemia |
0 |
1 (0.1) |
0 |
0 |
1(0.1) |
0 |
1 (0.1) [0.2] |
1 (0.2) [0.3] |
4 (0.2) [0.2] |
|
Retinal detachment |
0 |
1 (0.2) |
0 |
1 (0.1) |
1(0.2) |
1 (0.1) |
1 (0.2) [0.3] |
3 (0.5) [0.6] |
4 (0.2) [0.2] |
|
Eczema eyelids |
NR |
NR |
NR |
NR |
NR |
NR |
2 (0.2) [0.4] |
0 |
3 (0.1) [0.1] |
|
Eye swelling |
0 |
1 (0.2) |
0 |
1 (0.2) |
1 (0.2) |
1 (0.2) |
1 (0.2) [0.3] |
1 (0.2) [0.2] |
3 (0.1) [0.1] |
|
Dry eye |
4 (0.7) |
0d |
3 (0.6) |
0 |
0 |
0 |
0 |
0 |
2 (0.1) [0.1] |
|
Eye pain |
0 |
0 |
0 |
1 (0.1) |
0 |
1 (0.1) |
1 (0.1) [0.2] |
1 (0.1) [0.2] |
2 (0.1) [0.1] |
|
Eyelid edema |
0 |
1 (0.1) |
0 |
1 (0.2) |
1 (0.1) |
1 (0.2) |
1 (0.1) [0.2] |
1 (0.2) [0.3] |
2 (0.1) [0.1] |
|
Glaucoma |
1 (0.1) |
0 |
NR |
NR |
NR |
NR |
0 |
0 |
2 (0.1) [0.1] |
|
Hypermetropia |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
1 (0.2) [0.2] |
2 (0.1) [0.1] |
|
Keratitis |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.3] |
2 (0.1) [0.1] |
|
Ocular hypertension |
NR |
NR |
NR |
NR |
NR |
NR |
1 (0.2) [0.3] |
1 (0.2) [0.2] |
2 (0.1) [0.1] |
|
Swelling of eyelid |
2 (0.2) |
0 |
2 (0.2) |
0 |
0 |
0 |
0 |
0 |
2 (0.1) [0.1] |
|
Vitreous floaters |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
2 (0.4) [0.4] |
2 (0.1) [0.1] |
|
Angle closure glaucoma |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Blepharitis allergic |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Conjunctival irritation |
NR |
NR |
NR |
NR |
NR |
NR |
1 (0.1) [0.2] |
0 |
1 (0.0) [0.0] |
|
Corneal epithelial microcysts |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.3] |
1 (0.0) [0.0] |
|
Corneal erosion |
0 |
0 |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Eye allergy |
0 |
0 |
0 |
1 (0.1) |
0 |
1 (0.1) |
0 |
1 (0.1) [0.2] |
1 (0.0) [0.0] |
|
Eye inflammation |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Eye irritation |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
1 (0.2) [0.2] |
1 (0.0) [0.0] |
|
Eyelid disorder |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Keratoconus |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.3] |
1 (0.0) [0.0] |
|
Meibomian gland dysfunction |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Meibomianitis |
0 |
1 (0.1) |
0 |
0 |
1 (0.1) |
0 |
1 (0.1) [0.2] |
0 |
1 (0.0) [0.0] |
|
Noninfective conjunctivitis |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.3] |
1 (0.0) [0.0] |
|
Periorbital swelling |
0 |
0 |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Photopsia |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.2] |
1 (0.0) [0.0] |
|
Ulcerative keratitis |
NR |
NR |
NR |
NR |
NR |
NR |
1 (0.1) [0.2] |
0 |
1 (0.0) [0.0] |
|
Xerophthalmia |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Giant papillary conjunctivitis |
1 (0.1) |
0 |
1 (0.1) |
0 |
0 |
0 |
NR |
NR |
NR |
|
Visual acuity reduced |
1 (0.1) |
0 |
1 (0.1) |
0 |
0 |
0 |
NR |
NR |
NR |
Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; ext = extended; IR = incidence rate; NR = not reported; SOC = system organ class.
a Data through 16-week placebo-controlled period.
b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups.
c p≤.05 vs BARI 2 mg.
Placebo-Controlled Data Set
During the 16-week placebo-controlled period, there were
3 SAEs including
1 (0.1%) retinal detachment in the placebo group
1 (0.1%) cataract in the BARI 4 mg group, and
1 (0.2%) allergic conjunctivitis in the BARI 4 mg group
2 events, which led to temporary interruption of treatment including
1 (0.1%) conjunctival hemorrhage in the placebo group
1 (0.1%) cataract in the BARI 4 mg group, and
1 (0.2%) case of allergic conjunctivitis in the BARI 2 mg group, which led to permanent discontinuation from the study.4
One patient on BARI 2 mg who discontinued from the study due to allergic conjunctivitis, resumed treatment with BARI 4 mg in the BARI long-term extension study.4
The study-size adjusted percentages reported here were calculated for the adverse events to provide appropriate direct comparisons between treatment groups.
All BARI AD Data Set
In the All BARI data set, evaluating 2531 patients treated across all BARI doses studied in AD, there were 114 (4.5%) TEAEs related to eye disorders including
5 (0.2%) SAEs including
2 (0.1%) cataracts
1 (0.0%) allergic conjunctivitis
1 (0.0%) corneal erosion
1 (0.0%) retinal detachment
3 (0.1%) temporary treatment interruptions including
1 (0.0%) case of cataract
1 (0.0%) case of chalazion
1 (0.0%) case of retinal detachment, and
2 (0.1%) permanent discontinuations from study including
1 (0.0%) case of eye pruritis, and
1 (0.0%) case of swelling of eyelid.4
Treatment-Emergent Events Occurring Within the Conjunctivitis SMQ
In addition to the SOC and PT analyses, a cluster analysis was performed to assess groupings of nearly synonymous preferred and related terms associated with conjunctival disorders using standardized MedDRA queries.
Table 2 summarizes the TEAEs reported within the conjunctival disorders SMQ in the BARI AD clinical trial program .
Table 2. Treatment-Emergent Adverse Events Within the Conjunctival Disorders SMQ4
|
|
|
|
|
|
|
|
|
|
|
|
|
BARI
2 mg Placebo-Controlleda |
BARI
4 mg Placebo-Controlleda |
BARI
2 mg vs 4 mg |
BARI
2 mg vs 4 mg ext |
All
BARI AD |
||||
|
|
Placebo |
BARI
2 mg |
Placebo |
BARI
4 mg |
BARI
2 mg |
BARI
4 mg |
BARI
2 mg |
BARI
4 mg |
All
Doses |
|
Conjunctival Disorders (SMQ) |
18 (2.4) |
15 (2.0) |
15 (2.1) |
6 (1.2) |
12 (1.6) |
6 (1.2) |
21 (3.0) [4.9] |
18 (3.3) [4.6] |
96 (3.8) [4.3] |
|
Conjunctivitis |
2 (0.3) |
7 (0.9) |
2 (0.3) |
3 (0.6) |
6 (0.8) |
3 (0.6) |
10 (1.5) [2.4] |
8 (1.5) [2.2] |
39 (1.5) [1.7] |
|
Conjunctivitis allergic |
8 (1.0) |
4 (0.6) |
7 (0.9) |
1 (0.2) |
4 (0.6) |
1 (0.2) |
7 (1.0) [1.5] |
7 (1.2) [1.4] |
34 (1.3) [1.5] |
|
Seasonal allergy |
2 (0.2) |
3 (0.3) |
1 (0.1) |
0 |
1 (0.1) |
0 |
2 (0.3) [0.5] |
0 |
9 (0.4) [0.4] |
|
Conjunctival hemorrhage |
2 (0.3) |
0 |
2 (0.3) |
0 |
0 |
0 |
0 |
0 |
4 (0.2) [0.2] |
|
Conjunctival hyperemia |
0 |
1 (0.1) |
0 |
0 |
1 (0.1) |
0 |
1 (0.1) [0.2] |
1 (0.2) [0.3] |
4 (0.2) [0.2] |
|
Dry eye |
4 (0.7) |
0c |
3 (0.6) |
0 |
0 |
0 |
0 |
0 |
2 (0.1) [0.1] |
|
Keratitis |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.3] |
2 (0.1) [0.1] |
|
Conjunctival irritation |
NR |
NR |
NR |
NR |
NR |
NR |
1 (0.1) [0.2] |
0 |
1 (0.0) [0.0] |
|
Noninfective conjunctivitis |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.3] |
1 (0.0) [0.0] |
|
Xerophthalmia |
NR |
NR |
NR |
NR |
NR |
NR |
0 |
0 |
1 (0.0) [0.0] |
|
Giant papillary conjunctivitis |
1 (0.1) |
0 |
1 (0.1) |
0 |
0 |
0 |
NR |
NR |
NR |
Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; ext = extended; IR = incidence rate; MedDRA = Medical Dictionary for Regulatory Activities; NR = not reported; SMQ = Standardized MedDRA Query.
a Data through 16-week placebo-controlled period.
b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups.
Treatment-Emergent Adverse Events by Cluster in the Placebo-Controlled Data Set
In the 16-week placebo-controlled data set
more placebo-treated patients reported events in the cluster compared to the BARI-treated groups
the specific PT of conjunctivitis was more frequently reported in the BARI 2 mg group compared to the placebo and BARI 4 mg groups, and
none of the conjunctival disorders in the cluster were significantly higher in the BARI-treated groups compared to placebo.4
Treatment-Emergent Adverse Events by Cluster in the All BARI AD Data Set
In the All BARI AD data set, evaluating 2531 patients treated across all BARI doses studied in AD, there were
1 (0.0%) SAE reported due to allergic conjunctivitis, and
1 (0.0%) temporary interruption of BARI due to conjunctivitis.4
There were no treatment discontinuations reported due to conjunctivitis.4
Table 3. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials4
|
Analysis Set |
Description |
|
BARI 2 mg Placebo-Controlled Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7 |
Compares BARI 2 mg vs placebo Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to BARI 2 mg (n=721, PYE=210.6), or placebo (n=889, PYE=252.7). Treatment period was 0 to 16 weeks. |
|
BARI 4 mg Placebo-Controlled Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7 |
Compares BARI 4 mg vs placebo Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to BARI 4 mg (n=489, PYE=147.1), or placebo (n=743, PYE=211.8). Treatment period was 0 to 16 weeks. |
|
BARI 2 mg vs 4 mg Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7 |
Compares BARI 2 mg vs BARI 4 mg through 16 weeks Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to BARI 2 mg (n=576, PYE=169.1), or BARI 4 mg (n=489, PYE=147.1). Treated for 0 to 16 weeks during the placebo-controlled period. |
|
BARI 2 mg vs 4 mg Extended Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3 |
Compares BARI 2 mg vs BARI 4 mg including extended evaluations Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to BARI 2 mg (n=576, PYE=425.5), or BARI 4 mg (n=489, PYE=459.3). Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3. |
|
All BARI AD Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6 |
No between-group comparisons Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including BARI 1 mg (n=538, PYE=245.9) BARI 2 mg (n=1580, PYE=1129.5), and BARI 4 mg (n=914, PYE=872.8). Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo. No censoring of data at dose change. |
Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.
Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.
1. Thyssen JP, Toft PB, Halling-Overgaard AS, Gislason GH, Skov L, Egeberg A. Incidence, prevalence, and risk of selected ocular disease in adults with atopic dermatitis. J Am Acad Dermatol. 2017;77(2):280-286.e1. doi:10.1016/j.jaad.2017.03.003
2. Hsu JI, Pflugfelder SC, Kim SJ. Ocular complications of atopic dermatitis. Cutis. 2019;104(3):189-193. https://pubmed.ncbi.nlm.nih.gov/31675394/
3. Beck, K.M., Seitzman, G.D., Yang, E.J. et al. Ocular co-morbidities of atopic dermatitis. part I: associated ocular diseases. Am J Clin Dermatol. 2019;20:797–805. https://doi.org/10.1007/s40257-019-00455-5
4. Data on file, Eli Lilly and Company and/or one of its subsidiaries.
Glossary
AD = atopic dermatitis
BARI = baricitinib
MedDRA = Medical Dictionary for Regulatory Activities
PT = preferred term
SAE = serious adverse event
SMQ = standardized MedDRA query
SOC = system organ class
TEAE = treatment-emergent adverse event
▼ This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.
Date of Last Review: August 04, 2020
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