Olumiant ® (baricitinib)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information.For current prescribing 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 venous thromboembolism in the Olumiant® (baricitinib) rheumatoid arthritis clinical development program?

In all baricitinib treated patients with data up to 9.3 years of treatment and 14,744 patient-years of exposure, the incidence rate of venous thromboembolism was 0.5 per 100 patient-years at risk and remained stable over time.

UK_cFAQ_BAR133A_DVT_PE_RA
UK_cFAQ_BAR133A_DVT_PE_RA
en-GB

Information From the Label

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.1

Baricitinib should be used with caution in patients with risk factors for DVT/PE, such as

  • older age,
  • obesity,
  • a medical history of DVT/PE, or
  • patients undergoing surgery and immobilisation.1

If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.1

Deep vein thrombosis and PE have been included as uncommon ( ≥0.1% and <1%) adverse drug reactions for BARI in the Summary of Product Characteristics.1

Incidence and Risk of Venous Thromboembolism Events in the Rheumatoid Arthritis Clinical Development Program

Exclusion Criteria Related to Deep Vein Thrombosis and Pulmonary Embolism in the Baricitinib Rheumatoid Arthritis Phase 3 Clinical Development Program

Patients with a medical history of venous thromboembolism (VTE) were not specifically excluded from the phase 3 trials. Exclusion criteria related to cardiovascular events excluded patients who had

  • history or presence of cardiovascular, respiratory, or hematological disorders or any other serious or unstable illness that, in the opinion of the investigator, could constitute a risk when taking investigational product or could interfere with the interpretation of data, and
  • any major surgery within 8 weeks prior to study entry or would require major surgery during the study that, in the opinion of the investigator in consultation with Lilly or its designee, would pose an unacceptable risk to the patient.2

Deep Vein Thrombosis and Pulmonary Embolism in the Baricitinib Rheumatoid Arthritis Phase 3 Clinical Development Program

Analyses were conducted using integrated safety datasets including the

  • 7-study placebo-controlled dataset, which compares the safety of BARI 4 mg or 2 mg vs placebo through 24 weeks, and
  • ALL BARI RA dataset, the largest dataset that included 3770 patients with RA who received any dose of BARI from 9 randomized studies and 1 long-term extension study.3,4

Exploratory analyses in a subset of data from the ALL BARI RA dataset were also conducted in patients who had ever taken BARI 2 mg or 4 mg.4

More details on each dataset are provided in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials.

Incidence of Venous Thromboembolism Events in the Baricitinib Rheumatoid Arthritis Clinical Development Program presents the number of patients, incidence rates (IRs), and exposure-adjusted incidence rates (EAIRs) for the TEAEs and serious adverse events (SAEs) of VTE for the

  • 7-study dataset, and
  • the All BARI RA dataset.
Incidence of Venous Thromboembolism Events in the Baricitinib Rheumatoid Arthritis Clinical Development Program2-4

VTE

DVT

PE

TEAE
n [IR]

SAE
n [IR]

TEAE
n [IR]

SAE
n [IR]

TEAE
n [IR]

SAE
n [IR]

7-Study Placebo-Controlled Dataset (Weeks 0-24)

Placebo (N=1215)

0

0

0

0

0

0

Bari 2-mg (N=479)

0

0

0

0

0

0

Bari 4-mg (N=1142)

6 [1.3]

3 [0.6]

3 [0.6]

1 [0.2]

3 [0.6]

2 [0.4]

ALL BARI RA Dataset (PYE=14,744, median exposure=4.6 yrs, maximum exposure=9.3 yrs)

Phases 1-3
(N=3770)

73 [0.5]

51 [0.3]

52a [0.4]

29 [0.2]

39 [0.3]

35 [0.2]

Abbreviations: BARI = baricitinib; DVT = deep vein thrombosis; IR = incidence rate; PE = pulmonary embolism; PYE = patient-years of exposure; RA = rheumatoid arthritis; SAE = serious adverse event; TEAE = treatment-emergent adverse event; VTE = venous thromboembolism; yrs = years.


SAEs were any event meeting the International Conference on Harmonisation (ICH) E2A seriousness criteria. 

aDVT includes distal events below the knee.

7-Study Placebo-Controlled Dataset

A numeric imbalance in the number of treatment-emergent VTE events was noted for BARI 4 mg (n=6) compared with placebo (n=0) during weeks 0 to 24.3

Three of the events, specifically 1 DVT and 2 PEs, in the BARI 4-mg treatment group were considered SAEs due to hospitalization. The other 3 events, specifically 2 DVTs and 1 PE, did not require hospitalization.5,6

ALL BARI RA Dataset

In the ALL BARI RA dataset, 73 patients treated with BARI reported VTE events with an incidence (IR) of 0.5 per 100 patient-years at risk (PYR).4

The rates of VTE remained stable through exposures up to 9.3 years as seen in Venous Thromboembolism Incidence Rate Over Time for the All BARI RA Dataset.4

Venous Thromboembolism Incidence Rate Over Time for the All BARI RA Dataset4

Abbreviations: BARI = baricitinib; CI = confidence interval; IR = incidence rate; n/N = number of patients with events/total number of patients; PYR = patient-years at risk; RA = rheumatoid arthritis; VTE = venous thromboembolism.

Notes: Final analysis with total PYE = 14,744, median exposure 4.6 years, maximum exposure 9.3 years

In the ALL BARI RA dataset, there were

  • 52 patients with DVTs (IR=0.4), and
  • 39 patients with a PE (IR=0.3).4

A total of 14 patients had both DVT and PE concurrently. Ten patients had a recurrent VTE, all after stopping prophylactic anticoagulation treatment.2

There were 4 patients who died due to PE. None of the deaths were reported as related to BARI by the investigator.2

Incidence of Venous Thromboembolism by Baricitinib Dose

In the ALL BARI RA dataset, EAIR per 100 PYE were calculated for VTEs in the BARI 2 mg and BARI 4 mg subsets as seen in Exposure Adjusted Incidence Rates of Venous Thromboembolisms in the Baricitinib 2 mg and Baricitinib 4 mg subsets of the ALL BARI RA Analysis Set.

The EAIRs per 100 PYE for VTE were similar between patients in the BARI 2 mg and BARI 4 mg subgroups of the ALL BARI RA dataset as presented in Exposure Adjusted Incidence Rates of Venous Thromboembolisms in the Baricitinib 2 mg and Baricitinib 4 mg subsets of the ALL BARI RA Analysis Set.4

Exposure Adjusted Incidence Rates of Venous Thromboembolisms in the Baricitinib 2 mg and Baricitinib 4 mg subsets of the ALL BARI RA Analysis Set4

Ever on BARI 2 mg
(N=1077)
PYE=2678
EAIR (95% CI) 

Ever on BARI 4 mg
(N=3401)
PYE=11,872
EAIR (95% CI) 

ALL BARI RA
(N=3770)
PYE=14,744
IR (95% CI)

VTE (DVT and/or PE)

0.49 (0.26-0.83)

0.51 (0.39-0.66)

0.49 (0.38-0.61)

DVT

0.41 (0.21-0.73)

0.35 (0.25-0.48)

0.35 (0.26-0.45)

PE

0.26 (0.11-0.54)

0.27 (0.18-0.38)

0.26 (0.18-0.35)

Abbreviations: BARI = baricitinib; DVT = deep vein thrombosis; EAIR = exposure-adjusted incidence rate; IR = incidence rate; PE = pulmonary embolism; PYE = patient-years of exposure; RA = rheumatoid arthritis; VTE = venous thromboembolism.

Risk Factors for Venous Thromboembolism

Risk factors possibly associated with VTE events were evaluated from the ALL BARI RA dataset comparing the risks between patients with and without events and characteristics for these patients are provided in Potential Risk Factors for Patients With and Without Venous Thromboembolism in the ALL BARI RA Analysis Set (Total PYE = 14,774 PYE; Maximum Exposure = 9.3 years) .2,6

Factors from the analysis associated with an increased risk for VTE in the ALL BARI RA dataset included

  • age ≥50 years
  • body mass index (BMI) ≥30 
  • history of
    • VTE
    • malignancy
    • chronic cardiac failure, or
    • respiratory failure
  • estimated glomerular filtration rate <60 mL/min/1.73m2, and
  • severe mobility impairment.2,6

In the majority of patients with a reported VTE, concurrent risk factors for developing a VTE were present.2,6

These are among reported conventional risk factors for VTE for the general population.7

Neither baseline platelet count nor change in platelet count in the first couple of weeks of treatment or to maximum platelet count was associated with occurrence of VTE.2

Treatment-emergent thrombocytosis (defined as ≥600 billion cells/L) was seen in 8/73 (11%) patients with and 163/3697 (4.4%) patients without VTE. The role of BARI in this association was unclear because thrombocytosis was present in only few VTE cases.2

Coagulation Factor Abnormalities

Of the 49/3770 patients reporting VTE in the All BARI RA dataset representing a total of 10,127 PYE and up to 6.9 years maximum exposure,

  • 1 patient was found to have Factor V Leiden mutation
  • 1 patient was antiphospholipid antibody positive, and
  • 1 was known to have lupus anticoagulant.2

The patient with lupus anticoagulant had stopped taking warfarin in preparation for a cardiac catheterization procedure at the time of the DVT event.2

Laboratory Monitoring of Coagulation Factors

There are no requirements for laboratory monitoring of coagulation parameters specific to BARI treatment.2

In the BARI phase 3 clinical studies, coagulation parameters were not routinely assessed.2

Incidence of Venous Thromboembolism in the Published Literature and Claims Databases

The published IR of VTE among patients with RA in inpatient and outpatient settings ranges from 0.33 to 0.79 per 100 PYE. The overall VTE IR for BARI, 0.5 per 100 PYE, fell within the range reported in the literature for RA populations.5,8-10

To further characterize the VTE IR found for BARI, VTE IRs for the RA population from the Food and Drug Administration's (FDA’s) Sentinel program and Truven Marketscan administrative claims data were assessed. Both Sentinel and Truven administrative claims databases contain information on patients enrolled in US health plans. A subset of the Sentinel program representing 75 million enrolled patients identified over 69,000 users of RA medications. Truven represents over 110 million patients, from which over 205,000 patients with RA medications were identified.5,11-13

While not directly comparable with results from the BARI clinical trial program, venous thromboembolism IRs for RA patients treated with conventional and biologic DMARDs from Sentinel (IR range=0.76 – 3.08) and Truven (IR range=0.76 – 2.96) appear to be within a similar range including when comparing data by age for 50 to 59 year age group.11,12,14

Postmarketing Spontaneous Reports

Based on postmarketing spontaneous reports from February 2017, after the first global approval for RA, through February 2021

  • PE was rarely reported (≥0.01% and <0.1%), and
  • DVT was rarely reported (≥0.01% and <0.1%).2

Postmarketing cases of VTE were reported for both BARI 2 mg and BARI 4 mg doses and from many countries. The reporting rates were similar between BARI 2 mg and BARI 4 mg doses for VTE, DVT, and PE.2

As of September 2021, VTE had an overall reporting rate of 0.17 per 100 PYE in the postmarketing setting.2

Based on available information supplied at time of report and any follow-up, reported postmarketing cases were associated with one or more risk factors including

  • older age
  • previous history of VTE
  • post-surgical
  • lack of mobility
  • obesity
  • presence of malignancy, and/or
  • concomitant use of
    • corticosteroids
    • COX-2 inhibitor, and/or
    • estrogen.2

Postmarketing data do not necessarily represent the rate of occurrence of an AE in a treated population, but they represent a reporting rate of a particular AE to the company. Spontaneous reporting of AEs can be highly variable and is not appropriately controlled clinical information on which to base an assessment of whether a particular drug product is the causal agent of an event.15

Spontaneous reporting has limited use due to

  • lack of control population
  • under-reporting or reporting bias, and
  • missing or incomplete information regarding medical history or concomitant medications.15

References

1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3Genovese 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

4Taylor 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. Published online October 27, 2021. https://doi.org/10.1136/annrheumdis-2021-221276

5Eli Lilly and Company. Lilly FDA Advisory Committee Meeting NDA 207924 Briefing Document. https://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM605062.pdf. Accessed April 19, 2018.

6Taylor PC, Weinblatt ME, Burmester GR, et al. Cardiovascular safety during treatment with baricitinib in rheumatoid arthritis [published online January 21, 2019]. Arthritis Rheumatol. https://dx.doi.org/10.1002/art.40841

7Wakabayashi H, Hasegawa M, Niimi R, Sudo A. Clinical analysis of preoperative deep vein thrombosis risk factors in patients undergoing total hip arthroplasty. Thromb Res. 2015;136(5):855-858. http://doi.org/10.1016/j.thromres.2015.06.021

8Genovese 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):638. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1

9Choi HK, Rho YH, Zhu Y, et al. The risk of pulmonary embolism and deep vein thrombosis in rheumatoid arthritis: a UK population-based outpatient cohort study. Ann Rheum Dis 2013;72(7):1182-1187. http://dx.doi.org/10.1136/annrheumdis-2012-201669

10Ogdie A, Kay McGill N, Shin DB, et al. Risk of venous thromboembolism in patients with psoriatic arthritis, psoriasis and rheumatoid arthritis: a general population-based cohort study. Eur Heart J. 2018;39(39):3608-3614. http://dx.doi.org/10.1093/eurheartj/ehx145

11Maro JC, Menzin T, Hornbuckle J, et al. Risk of thromboembolism in rheumatoid arthritis patients treated with biologic and non-biologic DMARDs. Poster presented at: European League Against Rheumatism (EULAR) Annual Meeting; June 13-16, 2018; Amsterdam, Netherlands.

12Maro JC, Menzin T, Hornbuckle J, et al. Risk of thromboembolism in rheumatoid arthritis patients treated with biologic and non-biologic DMARDs. Poster presented at: American College of Rhuematology (ACR) Annual Meeting; October 19-24, 2018; Chicago, IL.

13Salinas CA, Mitchell L, Giles JT, et al. Risk of Venous Thromboembolism in Rheumatoid Arthritis Patients in Truven Marketscan Data (Jan 2010–Sept 2015) Treated with Biologic or Conventional Dmards [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/risk-of-venous-thromboembolism-in-rheumatoid-arthritis-patients-in-truven-marketscan-data-jan-2010-sept-2015-treated-with-biologic-or-conventional-dmards/

14Salinas CA, Mitchell L, Giles JT, et al. Risk of Venous Thromboembolism in Rheumatoid Arthritis Patients in Truven Marketscan Data (Jan 2010–Sept 2015) Treated with Biologic or Conventional Dmards. American College of Rhuematology (ACR) Annual Meeting; October 19-24, 2018; Chicago, IL. https://acrabstracts.org/abstract/risk-of-venous-thromboembolism-in-rheumatoid-arthritis-patients-in-truven-marketscan-data-jan-2010-sept-2015-treated-with-biologic-or-conventional-dmards/

15Goldman SA. Limitations and strengths of spontaneous reports data. Clin Ther. 1998;20(suppl 3):C40-C44. http://dx.doi.org/10.1016/S0149-2918(98)80007-6

Appendix

Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials2-4,8

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

  • BARI 4 mg (N=1142, [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or
  • placebo (N=1215, [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]).

Patients in the placebo group could have been taking

  • background MTX, or
  • in some studies, other conventional DMARD therapy.

Evaluation time periods included

  • through the 12-week placebo-controlled period in phase 2 studies
  • through 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and
  • through 24 weeks of assigned treatment or until rescue in phase 3 studies.

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).

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

  • BARI 4 mg (n=3401, PYE=11,872)
  • BARI 2 mg (n=1077, PYE=2678), and
  • BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies.

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.

Potential Risk Factors for Patients With and Without Venous Thromboembolism in the ALL BARI RA Analysis Set (Total PYE = 14,774 PYE; Maximum Exposure = 9.3 years)2 

Risk Factors at Baseline

Patients with VTE
N=73

Patients without VTE
N=3697

Incidence Rate per 100 PYR and 95% CI for patients with Risk Factors

Age

<50 years, n (%)

10 (13.7)

1366 (36.9)

0.18 [0.08, 0.32]

≥50 years, n (%)

63 (86.3)

2331 (63.1)

0.68 [0.52, 0.87]

BMI ≥30 kg/m2, n (%)

46 (63.0)

1054 (28.5)

1.07 [0.78, 1.43]

Baseline MTX use, n (%)

61 (83.6)

3023 (81.8)

0.48 [0.36, 0.61]

Baseline corticosteroid use, n (%)

42 (57.5)

1882 (50.9)

0.53 [0.38, 0.72]

Baseline COX-2 inhibitor use, n (%)

13 (17.8)

470 (12.7)

0.61 [0.32, 1.04]

Current smoker, n (%)

9 (12.3)

594 (16.1)

0.33 [0.15, 0.62]

History of VTE, n (%)

3 (4.1)

30 (0.8)

3.58 [0.74, 10.47]

History of malignancy, n (%)

5 (6.8)

47 (1.3)

3.04 [0.99, 7.10]

History of CHF or respiratory failure, n (%)

2 (2.7)

14 (0.4)

3.28 [0.40, 11.86]

History of diabetes mellitus, n (%)

8 (11.0)

327 (8.8)

0.64 [0.28, 1.27]

Screening eGFR <60 mL/min/1.73m2, n (%)

11 (15.1)

173 (4.7)

1.80 [0.90, 3.22]

Baseline EQ-5D mobility domain, Mean (SD)

2.7 (1.1)

2.3 (1.0

-

Baseline EQ-5D mobility ≥ severe, n (%)

18 (24.7)

450 (12.2)

0.98 [0.58, 1.55]

TE-thrombocytosis, n (%)

8 (11.0)

163 (4.4)

1.13 [0.49, 2.22]

Baseline platelet count (1000/μL), Mean (SD) 

286.9 (82.3)

289.3 (83.6)


Platelet CFB to the 2-week (1000/μL), Mean (SD)  

55.4 (53.9)

45.9 (56.4)

-

Platelet CFB to the maximum postbaseline (1000/μL), Mean (SD)

119.6 (71.9)

105.7 (75.5)

-

Abbreviations: BMI = body mass index; CFB = change from baseline; CHF = congestive heart failure; COX-2 = cyclooxygenase-2; eGFR = estimated glomerular filtration rate; EQ-5D = European Quality of Life-5 Dimensions-5 Level scores; MTX = methotrexate; N = number of patients in the analysis population; n = number of patients in the specified category; PE = pulmonary embolism; PY = patient-years; PYR = patient-years at risk; RA = rheumatoid arthritis; TE = treatment-emergent; VTE = venous thromboembolic events.

Date of Last Review: 14 October 2021


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