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Olumiant ® (baricitinib)
This information is intended for UK registered healthcare professionals only in response to your search for information. For current information for all Lilly products, including Summaries of Product Characteristics, Patient Information Leaflets and Instructions for Use, please visit: www.medicines.org.uk (England, Scotland, Wales) or www.emcmedicines.com/en-GB/northernireland/ (Northern Ireland).
Olumiant® (baricitinib): Efficacy and Safety in Elderly Patients with Rheumatoid Arthritis
In a post hoc analysis of 2 pooled phase 3 rheumatoid arthritis clinical trials, age did not affect the efficacy of baricitinib; however, more adverse events were reported in the elderly.
Content overview
- Important safety warning related to use of baricitinib in patients ≥65 years
- Dosing Recommendations for the Elderly Subpopulation
- Integrated Safety Dataset Analysis Based on Age
- Post Hoc Subgroup Analysis of Pooled RA-BEAM and RA-BUILD: Effect of Age on Efficacy and Safety
- Post Hoc Subgroup Analysis of Pooled RA-BEAM and RA-BUILD: Effect of Baseline Demographics on Efficacy
- Pooled Analysis of Phase 2 and Phase 3 Studies: Effect of Baseline Demographics on Efficacy
- Post Hoc Subgroup Analysis of RA-BEACON: Effect of Age on Efficacy
- References
Important safety warning related to use of baricitinib in patients ≥65 years
Considering the increased risk of1
- MACE,
- malignancies,
- serious infections, and
- all-cause mortality
in patients 65 years of age and older, as observed in a large randomised study of tofacitinib (another JAK inhibitor), baricitinib should only be used in these patients if no suitable treatment alternatives are available.1
Clinical experience in patients aged ≥ 75 years is very limited.1
Age ≥ 65 years or ≥ 75 years has no effect on baricitinib exposure (Cmax and AUC).1
For full prescribing information, please refer to the summary of product characteristics (SmPC).
Dosing Recommendations for the Elderly Subpopulation
A dose of 2 mg once daily is recommended for patients aged ≥ 65 years.1
A dose of 4 mg once daily may be considered for patients who do not achieve adequate control of disease activity with 2 mg once daily dose.1
Dose Modifications in Patients with Renal Impairment
Renal function was found to significantly affect baricitinib exposure.1
- The mean ratios of AUC in patients with mild and moderate renal impairment to patients with normal renal function are 1.41 (90 % CI: 1.15-1.74) and 2.22 (90 % CI: 1.81-2.73), respectively.1
- The mean ratios of Cmax in patients with mild and moderate renal impairment to patients with normal renal function are 1.16 (90 % CI: 0.92-1.45) and 1.46 (90 % CI: 1.17-1.83), respectively.1
The recommended dose is 2 mg once daily in patients with creatinine clearance between 30 and 60 mL/min. Baricitinib is not recommended for use in patients with creatinine clearance < 30 mL/min.1
Integrated Safety Dataset Analysis Based on Age
All BARI RA Dataset Description
The All BARI RA analysis set included 3770 patients with RA who received baricitinib at a variety of doses from 1 phase 1, 3 phase 2, and 5 phase 3 studies (RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, and RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with
- 14,744 PYE to baricitinib
- 15,114 patient-years overall observation including time on baricitinib and follow up
- median exposure of 4.6 years, and
- maximum exposure of 9.3 years.2
Incidence Rate of MACE by Age Category and Risk Factors
In the All BARI RA dataset, the IR of MACE was
- 1.13 per 100 PY in all patients ≥65 years
- 0.35 per 100 PY in patients >50 to <65 years with no CV risk factors, and
- 0.65 per 100 PY in patients >50 to <65 years with 1 CV risk factor (see ).3
Cardiovascular risk factors included current smoker, hypertension, HDL cholesterol <40 mg/dL, diabetes mellitus, and history of arteriosclerotic cardiovascular disease.3
Incidence Rate of VTE by Age Categroy
In the All BARI RA dataset, the IR of VTE was
- 1.0 per 100 PY in patients ≥65 years, and
- 0.58 per 100 PY in patients >50 to <65 years.3
In patients aged >50 to <65 years, higher IRs were observed in patients with a body mass index (BMI) >30 (1.41 per 100 PY) or severe mobility impairment (1.19 per 100 PY) (see ).3
Incidence Rate of Malignancy by Age Category
Serious Infection Results Based on Age
Incidence Rate of Safety Topics of Interest by Dose in 65 Years and Older
Data analyses were conducted for safety topics of special interest by baricitinib dose (2 mg and 4 mg) in patients 65 years and older from the RA clinical trials. Incidence rates were calculated for the "randomised" group and "as-treated" group since dose could have been up-titrated or down-titrated in the clinical trials based on response or rescue (see notes for numbers of patient included).3
In the randomized RA group, the number of MACE and VTE were low with both doses in patients ≥65 years old. The IR of serious infections in the group aged 65 years and older was
- 6.0 in patients randomized to 2 mg, and
- 4.0 in patients randomized to 4 mg (see for confidence intervals).3
In the as-treated group, the IRs for MACE, VTE, and mortality were similar between the baricitinib 4-mg and 2-mg group. The IR for serious infections was higher in the 4-mg group than in the 2-mg group. However, the as-treated groups were markedly different in disease severity and no reliable comparison can be made.3
provides details on the number, incidence, and confidence intervals of the adverse events by dose for each group.3
Post Hoc Subgroup Analysis of Pooled RA-BEAM and RA-BUILD: Effect of Age on Efficacy and Safety
Each of the 4 phase 3 studies in the clinical program evaluated a distinct treatment population of patients with moderate-to-severe RA.
- RA-BEGIN compared baricitinib 4 mg monotherapy, baricitinib 4 mg plus methotrexate (MTX), and MTX monotherapy in patients who had limited or no prior treatment with MTX and were naïve to other disease-modifying antirheumatic drugs (DMARDs).4
- RA-BEAM compared baricitinib 4 mg vs placebo or adalimumab, with background MTX, in patients with inadequate response to MTX.5
- RA-BUILD compared baricitinib 2 mg and 4 mg vs placebo, with background conventional synthetic DMARD (csDMARD) therapy, in patients with inadequate response to csDMARDs.6
- RA-BEACON compared baricitinib 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with an inadequate response to at least one TNF inhibitor, who may also have had an inadequate response to one or more non-TNF inhibitor biologic DMARDs.7
Overview of Pooled Analysis
A post hoc analysis of data from RA-BEAM and RA-BUILD was conducted to evaluate the efficacy and safety of using baricitinib in the elderly subpopulation, defined as patients 65 years or older. Combined data from both trials provided an overall sample of
- 714 patients in the baricitinib 4-mg group, and
- 716 patients in the placebo group.8
Efficacy and safety data are presented for patients aged <50, ≥50 and <65 years, and ≥65 years.8
Efficacy Results
Greater numerical improvements were seen for the efficacy endpoints in the baricitinib 4-mg group compared to the placebo group consistently across all age groups ().8
Baricitinib 4 mg <50 years (n=259) |
Baricitinib 4 mg ≥50 and <65 years |
Baricitinib 4 mg ≥65 years |
Placebo <50 years |
Placebo ≥50 and <65 years |
Placebo ≥65 years |
|
ACR20, % |
||||||
Week 12 |
69 |
66 |
68 |
37 |
41 |
43 |
Week 24 |
76 |
67 |
71 |
35 |
40 |
40 |
ACR50, % |
||||||
Week 12 |
41 |
41 |
42 |
15 |
16 |
14 |
Week 24 |
54 |
45 |
47 |
19 |
20 |
24 |
ACR70, % |
||||||
Week 12 |
18 |
17 |
24 |
5 |
4 |
4 |
Week 24 |
34 |
24 |
27 |
7 |
9 |
8 |
CDAI, week 24, % |
||||||
LDA (≤10) |
52 |
48 |
53 |
19 |
23 |
27 |
Remission (≤2.8) |
16 |
15 |
18 |
3 |
5 |
4 |
SDAI, week 24, % |
||||||
LDA (≤11) |
54 |
49 |
53 |
19 |
24 |
27 |
Remission (≤3.3) |
17 |
14 |
18 |
3 |
4 |
3 |
Abbreviations: ACR20 = American College of Rheumatology 20% response criteria; ACR50 = American College of Rheumatology 50% response criteria; ACR70 = American College of Rheumatology 70% response criteria; CDAI = Clinical Disease Activity Index; LDA = low disease activity; SDAI = Simplified Disease Activity Index.
Safety Results
In both the baricitinib 4-mg and placebo groups, elderly patients had more adverse events (AEs), serious adverse events (SAEs), and discontinuations due to AEs at week 24 ().8
Baricitinib 4 mg <50 years |
Baricitinib 4 mg ≥50 and <65 years |
Baricitinib 4 mg ≥65 years |
Placebo <50 years |
Placebo ≥50 and <65 years |
Placebo ≥65 years |
|
Patients with ≥1 AE, n (%) |
229 (88) |
296 (93) |
135 (99) |
212 (84) |
326 (93) |
111 (98) |
Discontinuation due to AE or death, n (%) |
6 (2) |
18 (6) |
12 (9) |
6 (2) |
14 (4) |
7 (6) |
Death, n (%) |
0 |
1 (<1) |
1 (1) |
0 |
2 (1) |
0 |
Serious AEs, n (%) |
8 (3) |
15 (5) |
12 (9) |
10 (4) |
11 (3) |
12 (11) |
Serious infections, n (%) |
3 (1) |
2 (1) |
4 (3) |
4 (2) |
5 (1) |
2 (2) |
Cardiac disorders, n (%) |
0 |
2 (1) |
2 (2) |
1 (<1) |
1 (<1) |
2 (2) |
Patients with ≥1 infection, n (%) |
99 (38) |
125 (39) |
48 (35) |
89 (35) |
86 (25) |
38 (34) |
Herpes zoster, n (%) |
2 (1) |
5 (2) |
3 (2) |
0 |
2 (1) |
0 |
Abbreviation: AE = adverse event.
Serious AEs requiring hospitalization were reported in
- 1 patient due to thrombophlebitis in the baricitinib 4-mg <50-year age group, and
- 6 patients due to fractures related to falls with 2 patients in the ≥65-year age group.8
None of these patients discontinued the study, and all of these events resolved.8
There were 4 deaths in patients ≥50 years of age due to
- subarachnoid hemorrhage and renal failure in the placebo ≥50 and <65 group (n=2)
- circulatory failure in the baricitinib-4 mg ≥50 and <65 group (n=1), and
- pneumonia in the baricitinib 4-mg elderly group (n=1).8
Post Hoc Subgroup Analysis of Pooled RA-BEAM and RA-BUILD: Effect of Baseline Demographics on Efficacy
Overview of Post Hoc Analysis
This post hoc analysis assessed the effect of baseline demographics, including age, on the response to baricitinib treatment in patients with RA and an inadequate response to prior csDMARDs.9
Data was pooled from 2 phase 3 double-blind, randomized controlled trials for
- 714 patients who received baricitinib 4 mg, and
- 716 patients who received placebo.9
Efficacy Results
Patients in the baricitinib 4-mg group had improved efficacy compared with patients in the placebo group regardless of age group (). None of the reported baseline demographic characteristics had a substantial effect on the reported efficacy outcomes.9
ACR20 Response PBO |
ACR20 Response BARI 4 mga |
Change from Baseline in DAS28-hsCRP PBO |
Change from Baseline in DAS28-hsCRP BARI 4 mga |
Patients Achieving SDAI ≤11 PBO |
Patients Achieving SDAI ≤11 BARI 4 mga |
|
Age group (years) |
||||||
<65 |
237/603 |
387/578 |
-1.0 (0.05) |
-2.1 (0.05) |
102/603 |
221/578 |
≥65 |
49/113 |
92/136 |
-1.2 (0.11) |
-2.4 (0.10) |
20/113 |
63/136 |
≥75 |
4/14 28.6% |
16/22 72.7% |
0.2 (0.67) |
-1.6 (0.59) |
2/14 14.3% |
10/22 45.5% |
Abbreviations: ACR20 = American College of Rheumatology 20% response criteria; BARI = baricitinib; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein; LSM = least squares mean; PBO = placebo; SDAI = Simplified Disease Activity Index.
aOnly the baricitinib 4-mg dose was included in the subgroup analysis although baricitinib 2 mg was evaluated in RA-BUILD.
Safety Results
The proportions of patients ≥65 years of age and <65 years of age who reported AEs or SAEs or discontinued from the study due to an AE were similar in the baricitinib 4-mg and placebo groups.9
Pooled Analysis of Phase 2 and Phase 3 Studies: Effect of Baseline Demographics on Efficacy
Effect of Age on Efficacy of Baricitinib
Overview of Pooled Analysis
Demographic subgroups were also evaluated using pooled data from
- 3 phase 2 studies
- JADC
- JADA,
- JADN, and
- 2 phase 3 studies, RA-BEAM and RA-BUILD.10
Patients included in this analysis were
- inadequate responders to csDMARDs, and
- were administered baricitinib 4 mg (n=881) or placebo (n=803) on a background of csDMARD therapy.10
The objective was to assess the consistency of the BARI treatment effect across baseline demographic subgroups using a large pooled sample of patients with similar treatment history.10
Interaction p values ≤.10 were considered indicative of a possible interaction between treatment and subgroup.10
Efficacy Results
Efficacy outcomes were evaluated across several baseline demographics including age.10
Treatment with baricitinib 4 mg daily was associated with a treatment benefit compared with placebo across subgroups based on age ().10
ACR50 Response PBO |
ACR50 Response BARI 4 mg |
ACR50 Response OR (95% CI) |
DAS28-hsCRP ≤3.2 PBO |
DAS28-hsCRP ≤3.2 BARI 4 mg |
DAS28-hsCRP ≤3.2 OR (95% CI) |
HAQ-DI Change From Baseline PBO |
HAQ-DI Change From Baseline BARI 4 mg |
HAQ-DI Change From Baseline LSMD (95% CI) |
|
Overall study population |
127/881 (14.4) |
330/803 (41.1) |
4.1 (3.3, 5.2)a |
146/881 (16.6) |
352/803 (43.8) |
4.2 (3.3, 5.3)a |
-0.25 (0.03) [868] |
-0.53 (0.03) [792] |
-0.28 (-0.33, -0.23)a |
Age (years) |
|||||||||
<65 |
109/750 (14.5) |
265/650 (40.8) |
4.03 (3.11, 5.23) |
122/750 (16.3) |
278/650 (42.8) |
4.07 (3.16, 5.25) |
-0.24 (0.03) [739] |
-0.53 (0.03) [641] |
-0.28 (-0.34, -0.23) |
≥65 |
18/131 (13.7) |
65/153 (42.5) |
4.59 (2.53, 8.30) |
24/131 (18.3) |
74/153 (48.4) |
4.65 (2.61, 8.26) |
-0.23 (0.06) [129] |
-0.52 (0.06) [151] |
-0.29 (-0.40, -0.17) |
<75 |
126/867 (14.5) |
319/779 (40.9) |
NPb |
145/867 (16.7) |
337/779 (43.3) |
NP |
-0.25 (0.03) [854] |
-0.54 (0.03) [769] |
NP |
≥75 |
1/14 (7.1) |
11/24 (45.8) |
NP |
1/14 (7.1) |
15/24 (62.5) |
NP |
-0.19 (0.16) [14] |
-0.16 (0.12) [23] |
NP |
Abbreviations: ACR50 = American College of Rheumatology 50% response criteria; BARI = baricitinib; DAS28-hsCRP = 28-joint Disease Activity Score based on high-sensitivity C-reactive protein; HAQ-DI = Health Assessment Questionnaire-Disability Index; LSM = least squares mean; N-obs = number observed; NP = not provided; PBO = placebo; wt = weight.
ap<.001 for BARI 4 mg vs placebo in overall pooled population
bWhen logistic regression sample size requirements are not met, odds ratio and 95% CI are not provided within a subgroup
Post Hoc Subgroup Analysis of RA-BEACON: Effect of Age on Efficacy
Overview of Post Hoc Subgroup Analysis
A subgroup analysis of data from RA-BEACON assessed the efficacy of baricitinib 2 mg or 4 mg daily by baseline characteristics including age at weeks 12 and 24. Interaction p values ≤ .10 were considered indicative of a possible interaction between treatment and subgroup.11
The analysis did not assess the incidence of AEs by baseline age.11
Efficacy Results
The analysis did not find a significant consistent effect of baseline age for American College of Rheumatology 20% response criteria (ACR20) or Clinical Disease Activity Index ≤10 (CDAI ≤10) at week 12 or 24 between baricitinib 4 mg and placebo or baricitinib 2 mg and placebo ().11
|
Age, <65 yearsa |
Age, ≥65 yearsa |
Percent of patients achieving ACR20, n/N (%) |
||
BARI 2 mg |
||
Week 12 |
67/139 (48) |
18/35 (51) |
Week 24 |
61/139 (44) |
17/35 (49) |
BARI 4 mg |
||
Week 12 |
70/136 (51) |
28/41 (68) |
Week 24 |
58/136 (43) |
24/41 (59) |
PBO |
||
Week 12 |
38/136 (28) |
10/40 (25) |
Week 24 |
35/136 (26) |
13/40 (30) |
Percent of patients achieving CDAI ≤10, n/N (%) |
||
BARI 2 mg |
||
Week 12 |
34/139 (24) |
7/35 (20) |
Week 24 |
30/139 (22) |
10/35 (29) |
BARI 4 mg |
||
Week 12 |
32/136 (24) |
17/41 (41) |
Week 24 |
35/136 (26) |
20/41 (49) |
PBO |
||
Week 12 |
16/136 (12) |
3/40 (8) |
Week 24 |
22/136 (16) |
5/40 (13) |
Abbreviations: ACR20 = American College of Rheumatology 20% response criteria; BARI = baricitinib; CDAI = Clinical Disease Activity Index; PBO = placebo.
ap=.043 for interaction of age for BARI 4 mg vs placebo at 24 weeks (p≤.01 was considered significant).
References
1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Taylor PC, Takeuchi T, Burmester GR, et al. Safety of baricitinib for the treatment of rheumatoid arthritis over a median of 4.6 and up to 9.3 years of treatment: final results from long-term extension study and integrated database. Ann Rheum Dis. 2022;81(3):335-343. https://doi.org/10.1136/annrheumdis-2021-221276
3Data on file, Eli Lilly and Company and/or one of its subsidiaries.
4Fleischmann R, Schiff M, van der Heijde D, et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 2017;69(3):506-517. http://dx.doi.org/10.1002/art.39953
5Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652-662. http://dx.doi.org/10.1056/NEJMoa1608345
6Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76(9):1634. http://dx.doi.org/10.1136/annrheumdis-2016-210094corr1
7Genovese MC, Kremer J, Zamani O, et al. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243-1252. http://dx.doi.org/10.1056/NEJMoa1507247
8Fleischmann R, Alam J, Arora V, et al. Safety and efficacy of baricitinib in elderly patients with rheumatoid arthritis. RMD Open. 2017;3(2):1-5. http://dx.doi.org/10.1136/rmdopen-2017-000546
9Kremer JM, Schiff M, Muram D, et al. Response to baricitinib therapy in patients with rheumatoid arthritis with inadequate response to csDMARDs as a function of baseline characteristics. RMD Open. 2018;4(1):e000581. http://dx.doi.org/10.1136/rmdopen-2017-000581
10Dougados M, Rooney TP, Xie L, et al. Efficacy response to baricitinib based on baseline characteristics in patients who are inadequate responders to conventional DMARDs [abstract]. Arthritis Rheumatol. 2017;69(suppl 10):512. http://acrabstracts.org/abstract/efficacy-response-to-baricitinib-based-on-baseline-characteristics-in-patients-who-are-inadequate-responders-to-conventional-dmard/
11Genovese MC, Kremer JM, Kartman C, et al. Response to baricitinib based on prior biologic use in patients with refractory rheumatoid arthritis. Rheumatology (Oxford). 2018;57(5):900-908. https://doi.org/10.1093/rheumatology/kex489
Date of Last Review: 17 February 2023