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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).
What is the incidence of infection with Olumiant® (baricitinib) treatment in rheumatoid arthritis?
The incidence rate (IR) of infections was 17.1 per 100 patient-years at risk (PYR) and 2.6 per 100 PYR for serious infections in all baricitinib dataset up to 9.3 years. The IR remained stable over time.
Content overview
- Special warnings and precautions regarding infections
- Incidence of infections in placebo-controlled trials and long term baricitinib exposure
- Incidence of serious infections in patients at-risk
- Incidence of infections in real-world studies
- Ongoing baricitinib safety trials
- References
- Appendix: Integrated analysis datasets rheumatoid arthritis clinical trials
Special warnings and precautions regarding infections
Serious and sometimes fatal infections have been reported in patients receiving other JAK inhibitors.1
Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo. In rheumatoid arthritis clinical studies, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.1
The risks and benefits of treatment should be carefully considered prior to initiating baricitinib in patients with active, chronic or recurrent infections.1
If an infection develops, the patient should be monitored carefully and therapy should be temporarily interrupted if the patient is not responding to standard therapy. Treatment should not be resumed until the infection resolves.1
As there is a higher incidence of infections in the elderly and in the diabetic populations in general, caution should be used when treating the elderly and patients with diabetes. In patients over 65 years of age, baricitinib should only be used if no suitable treatment alternatives are available.1
Please refer to section 4.8 of the Olumiant Summary of Product Characteristics for further information on this topic.
Screening for tuberculosis
Patients should be screened for tuberculosis (TB) before starting therapy.1
The IR for tuberculosis in All-bari-RA (0.1, 95%CI 0.08 to 0.20) (table 1) did not increase with prolonged exposure. No cases were reported with 2mg , and the events occurred almost exclusively in endemic countries (Argentina, China, India, Lithuania, Mexico, Russia, South Africa, South Korea and Taiwan), with one report in the USA.2
Screening for herpes zoster
If a patient develops herpes zoster, treatment should be temporarily interrupted until the episode resolves.1
The IR for herpes zoster (3.0, 95%CI 2.70 to 3.28) remained essentially unchanged from our previous report and did not increase with prolonged exposure. The IR for herpes zoster was highest in Asia (IR 5.2, 95%CI 4.42 to 6.01). Majority of the herpes zoster cases were mild (39.8%) or moderate (54.5%) in severity and occurred mostly in patients who were older (75.1% in patients ≥50 years), without prior episodes (96.0%) or without prior vaccination (96.1%), and 91% of the patients recovered.2
Screening for viral hepatitis
Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with baricitinib.1
- Patients with evidence of active hepatitis B or C infection were excluded from clinical trials.
- Patients, who were positive for hepatitis C antibody but negative for hepatitis C virus RNA, were allowed to participate.
- Patients with hepatitis B surface antibody and hepatitis B core antibody, without hepatitis B surface antigen, were also allowed to participate; such patients should be monitored for expression of hepatitis B virus (HBV) DNA.
- If HBV DNA is detected, a liver specialist should be consulted to determine if treatment interruption is warranted.
Though HBV reactivation was seen in patients with RA treated with DMARDs, including baricitinib, who had serology suggestive of prior infection, reactivation was transient even with continued baricitinib treatment and did not account for any clinically relevant AEs.3
Incidence of infections in placebo-controlled trials and long term baricitinib exposure
Baricitinib was evaluated in up to 14.744 patient-years of exposure and up to 9.3 years.2 Please find an overview about the datasets used to evaluate safety in the rheumatoid arthritis clinical trials in Appendix: Integrated analysis datasets rheumatoid arthritis clinical trials. All incidence rates were calculated as number of patients with an event per 100 patient-years of risk.
|
Placebo-controlled |
4-Study extended dataset |
All-BARI-RA |
|||
n (EAIR)a |
Placebo |
BARI 2 mgb |
BARI 4 mg |
BARI 2 mgc |
BARI 4 mgd |
N=3770 |
All TE infection |
340 (75.4) |
156 (84.0) |
423 (89.7) |
238 (30.2) |
271 (34.0) |
2590 (17.1) |
Led to temporary treatment interruption |
54 (12.0) |
34 (18.3) |
69 (14.6) |
71 (9.2) |
75 (9.6) |
827 (5.5) |
Led to permanent discontinuation |
8 (1.8) |
7 (3.8) |
23 (4.9) |
12 (1.5) |
22 (2.8) |
185 (1.2) |
Serious infection,e n, (IR) |
19 (4.1) |
8 (4.2) |
19 (4.0) |
22 (2.8) |
33 (4.1) |
372 (2.5) |
Infection leading to death |
4 (0.9) |
0 |
3 (0.6) |
1 (0.1) |
1 (0.1) |
19 (0.1) |
Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; IR = incidence rate; PYE = patient-years of exposure; RA = rheumatoid arthritis; TE = treatment emergent.
aExposure-adjusted incidence rate unless otherwise specified.
bBaricitinib 2-mg data in the placebo-controlled analysis set are derived from 4 studies in which both BARI 2 mg and 4 mg were options during randomization.
cIncludes data through September 1, 2019 with a maximum of 2370 days exposure.
dIncludes data through September 1, 2019 with a maximum of 3085 days exposure.
eIdentified as serious by International Conference on Harmonization criteria and included pneumonia, (EAIR 0.56), Herpes Zoster (EAIR 0.29), urinary tract infection (EAIR 0.17), cellulitis (EAIR 0.15), sepsis (EAIR 0.13), and andgastroenteritis (EAIR 0.11).
Incidence of serious infections in patients at-risk
In the All-BARI-RA dataset, 2619 out of 3770 patients were considered at-risk. This was defined as being ≥65 years old or having at least one of the following risk factors:
- atherosclerotic cardiovascular disease,
- diabetes mellitus,
- hypertension,
- current smoking,
- high-density lipoprotein cholesterol less than 40 mg/dL,
- body mass index at least 30,
- poor mobility on EuroQol-5 Dimension, and history of malignancy ().5
Event, n (IR per 100 PY) |
All-BARI-RA |
Patients at-riska |
Serious infection |
372 (2.58) |
297 (2.95) |
Abbreviations: BARI = baricitinib; IR = incidence rate; PY = patient years; RA = rheumatoid arthritis;
aDefined as being ≥65 years old or having at least one of the following risk factors: atherosclerotic cardiovascular disease, diabetes mellitus, hypertension, current smoking, high-density lipoprotein cholesterol less than 40 mg/dL, body mass index at least 30, poor mobility on EuroQol-5 Dimension, and history of malignancy
Incidence of infections in real-world studies
Retrospective observational studies
B023, a multi-database, observational retrospective cohort study, was initiated to compare the safety of baricitinib with tumor necrosis factor inhibitors (TNFi) for risk of venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and serious infection in patients with rheumatoid arthritis (RA) in routine care. A meta-analysis was used to combine results across 14 real-world data sources, including 3 disease registries, 8 administrative claims databases, and 3 national healthcare systems, in Europe, the United States, and Japan.6
Of 9013 eligible patients treated with baricitinib, 7606 (84%) were propensity score-matched 1:1 with patients treated with TNFi and contributed
- 5879 person-years of baricitinib exposure, and
- 6512 person-years of TNFi exposure.6
After propensity score matching, there was little to no difference in the prevalence of measured risk factors between treatment cohorts for each outcome analyzed. 6
Of the 321 patients who experienced serious infection, 176 were treated with baricitinib over a mean follow-up period of 10 months for baricitinib-treated patients and 11 months for TNFi-treated patients.6
The overall IRR of serious infection was numerically but not significantly greater for baricitinib vs TNFi (IRR=1.36; 95% CI, 0.86 to 2.13).6
The IRD between baricitinib and TNFi was not statistically significant (IRD=0.57 [95% CI, -0.07 to 1.21] per 100 person-years), and estimates that an additional 6 serious infections per year could be expected for every 1000 patients treated with baricitinib instead of a TNFi.6
The distribution of time to serious infection was variable, ranging from 1 to 1460 days.6
In a nationwide register-based cohort study in Sweden (ARTIS programme) that included patient with RA that started a treatment with b/ts DMARDs between 1st of January 2010 and 31 December 2020, and followed until 30 June of 2021 showed7:
- there were few significant differences between baricitinib or tofacitinib and bDMARDs regarding general infections (barictinib HR vs etanercept 0.98 (0.75 -1.29))
- JAKi were associated with higher rates of hospital-treated herpes zoster (baricitinib HR vs etanercept, 3.82(95% CI 2.05 to 7.09) and tofacitinib HR vs etanercept 4.00 (1.59 to 10.06)).
The data from the ARTIS programme tsDMARDs currently used in RA have acceptable and largely similar safety profiles but differences exist in particular concerning tolerability, specific infection risks and for specific serious but rare outcomes.7
In an ongoing, 3-year, all-case PMS study conducted in Japan since baricitinib was initially marketed in September 2017 and is a condition of the drug’s approval in Japan. During 24 weeks observation period AEs and ADRs occurred in 1271 (26.87%) and 967 (20.44%) patients, respectively. Among the AEs of special interest, the most common were herpes zoster (3.09%), hepatic function disorder (2.77%), and serious infection (1.90%). Of the 146 patients with herpes zoster, 50 patients used systemic antiviral drugs, four patients had disseminated varicella zoster virus infection (all recovered), and four patients had postherpetic neuralgia (three patients were recovered or recovering) within 24 weeks of starting baricitinib treatment. The most common types of serious infection were pneumonia (0.49%), herpes zoster (0.32%), and pneumonia bacterial (0.23%). For herpes zoster, the incidence was 3.04% for ADRs and 0.44% for serious events.8
Of 13,491 RA patients followed-up in RABBIT registry, 2274 with an age > 70 years were included in the analysis. Patient population characteristics were well-balanced between JAKi and TNFi groups. 626 serious infections (SI) were observed in 425 of these patients. Glucocorticoid use, higher DAS28-ESR values, COPD or pulmonary fibrosis, chronic kidney disease and diabetes mellitus were associated with an increased risk of SI. JAKi use was not associated with an increased risk of SI in elderly patients.9
Ongoing baricitinib safety trials
Two randomized, controlled, open-label, phase 3b/4 studies, RA-BRIDGE (NCT03915964) and RA-BRANCH (NCT04086745), are evaluating the safety of baricitinib 2 and 4 mg compared to adalimumab or etanercept in patients with rheumatoid arthritis who had an inadequate response or intolerance to at least one DMARD. The outcome measures are the time from first dose of study treatment to the first event of:
In RA-BRIDGE and RA-BRANCH, patients had at least 1 of the following baseline characteristics:
RA-BRIDGE includes an estimated enrollment of 2600 participants from sites in the United States and outside the United States. The estimated primary completion date is April 2025.11
RA-BRANCH is currently recruiting patients in the United States. The estimated enrollment will be 1300 patients and the estimated primary completion date is December 2024.10
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
3Harigai M, Winthrop K, Takeuchi T, et al. Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis. RMD Open. 2020;6:e001095. http://dx.doi.org/10.1136/rmdopen-2019-001095
4Data on file, Eli Lilly and Company and/or one of its subsidiaries.
5Taylor, P.C., Bieber, T., Alten, R. et al. Baricitinib Safety for Events of Special Interest in Populations at Risk: Analysis from Randomised Trial Data Across Rheumatologic and Dermatologic Indications. Adv Ther (2023). https://doi.org/10.1007/s12325-023-02445-w
6Salinas CA, Louder A, Polinski J, et al. Evaluation of VTE, MACE, and serious infections among patients with RA treated with baricitinib compared to TNFi: a multi-database study of patients in routine care using disease registries and claims databases. Rheumatol Ther. Published online November 13, 2022. https://doi.org/10.1007/s40744-022-00505-1
7Frisell T, Bower H, Morin M, et al. Safety of biological and targeted synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis as used in clinical practice: results from the ARTIS programme [published online ahead of print, 2023 Feb 14]. Ann Rheum Dis. 2023;ard-2022-223762. http://dx.doi.org/10.1136/ard-2022-223762
8Takagi M, Atsumi T, Matsuno H, et al. Safety and Effectiveness of Baricitinib for Rheumatoid Arthritis in Japanese Clinical Practice: 24-Week Results of All-Case Post-Marketing Surveillance [published online ahead of print, 2022 Aug 6]. Mod Rheumatol. 2022;roac089. https://doi.org/10.1093/mr/roac089
9Strangfeld A, Manger B, Worsch M, et alOP0116 ELDERLY PATIENTS ARE NOT AT INCREASED RISK OF SERIOUS INFECTIONS WHEN RECEIVING BDMARDS OR JAK INHIBITORS COMPARED TO CSDMARD TREATMENTAnnals of the Rheumatic Diseases 2021;80:64-65.
10A study of baricitinib in participants with rheumatoid arthritis (RA-BRANCH). ClinicalTrials.gov identifier: NCT04086745. Updated April 19, 2022. Accessed March 14, 2022. https://clinicaltrials.gov/ct2/show/NCT04086745
11A study of baricitinib (LY3009104) in participants with rheumatoid arthritis (RA-BRIDGE). ClinicalTrials.gov identifier: NCT03915964. Updated June 10, 2021. Accessed March 2, 2022. https://clinicaltrials.gov/ct2/show/NCT03915964
12Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 8.4 years: an updated integrated safety analysis. Ann Rheum Dis. 2020;79(suppl 1):642-643. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1
13Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis. Lancet Rheumatol. 2020;2(6):E347-E357. https://doi.org/10.1016/S2665-9913(20)30032-1
Appendix: Integrated analysis datasets rheumatoid arthritis clinical trials
Analysis Set |
Descriptiona |
7-Study Placebo-Controlled Dataset Studies: JADC, JADA, JADN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE |
Compares BARI 4 mg vs placebo Includes patients with RA from 3 phase 2 and 4 phase 3 studies who were randomized to
Patients in the placebo group could have been taking
Evaluation time periods included
BARI 2 mg Analysis Set BARI 2 mg data is derived from 4 studies in which both BARI 2 mg (N=479, [exposure through 24 weeks: PYE=185.8, median exposure=168 days, maximum exposure=197 days]) and BARI 4 mg were options during randomization (JADA, JADN, RA-BUILD, RA-BEACON). |
4-Study Extended Dataset Studies: JADA, JADN, RA-BUILD, RA-BEACON, RA-BEYOND (extension) |
Compares BARI 4 mg vs BARI 2 mg including extended evaluations Includes patients with RA from 2 phase 2 and 2 phase 3 studies and any further exposure for those patients in the phase 3 extension study, RA-BEYOND, who were randomized to
Evaluation time period included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified. |
All BARI RA Dataset Studies: JADB, JADC, JADA, JADN, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE, RA-BEYOND (extension) |
No between-group comparisons Includes patients with RA (N=3770, PYE=14,744 PY exposure to BARI and 15,114 PY overall observation including time on BARI and follow up, median exposure=4.6 yrs, maximum exposure=9.3 yrs) from 1 phase 1b, 3 phase 2, 5 phase 3 studies, and 1 phase 3 extension study who received BARI at a variety of doses, including
Patients had to have received at least 1 dose of BARI and could have received different doses throughout the trials. Evaluation time period is all exposure time points including after rescue or changes in study drug unless otherwise specified. |
Abbreviations: BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PY = patient-years; PYE = patient-years of exposure; QD = once daily; RA = rheumatoid arthritis.
aPatients with renal function impairment who were randomized to BARI 4 mg, but treated with the 2-mg dose were analyzed in the BARI 4-mg group.
Date of Last Review: 05 June 2023