Olumiant ® (baricitinib) tabletter

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Olumiant® (baricitinib): venösa tromboembolismhändelser i det kliniska utvecklingsprogrammet

Venös tromboembolism (VTE) har rapporterats hos patienter som fått baricitinib i det kliniska utvecklingsprogrammet.

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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

Venous Thromboembolism Events in the in the Rheumatoid Arthritis Clinical Development Program

7-Study Placebo-Controlled Dataset

The 7-study pooled dataset included patients with RA randomized to BARI 4 mg (N=1142, PYE=471.8) or placebo (N=1215, PYE=450.8) from 3 phase 2 studies and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON, and RA-BALANCE). Patients could have been taking background MTX or other conventional DMARDs. Evaluation time periods included through

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

Data from BARI 2 mg (N=479, PYE=185.8) were derived from 4 of these studies in which both BARI 2 mg and BARI 4 mg were options during randomization (2 phase 2 studies as well as RA-BUILD and RA-BEACON).2

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 24.2

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.3,4

Details for each case are presented in Incidence of VTE Events in the BARI RA Clinical Development Program.

4-Study Extended Dataset

The extended dataset included patients with RA randomized to BARI 4 mg (N=479, PYE=781.1) or BARI 2 mg (N=479, PYE=774.9) from 2 phase 2 and 2 phase 3 studies (RA-BUILD, RA-BEACON) and 1 long term extension study (RA-BEYOND). The evaluation time periods included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified. Data were censored at rescue or dose change.5

    As shown in Incidence of VTE Events in the BARI RA Clinical Development Program, no dose-response relationship was observed for VTE events. The VTE IR was

    • 0.6 for BARI 2 mg, and
    • 0.5 for BARI 4 mg.5

    All BARI RA Dataset

    The All BARI RA analysis set included 3770 patients with RA who received BARI 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

    • 13,148 PYE
    • median exposure of 4.2 years
    • maximum exposure of 8.4 years, and
    • data through September 1, 2019.6,7

    With a maximum of 8.4 years of exposure, 60 (1.6%) patients treated with BARI reported VTE events with an IR of 0.5 per 100 PY of observation time.

    • Forty-one (1.1%) patients treated with BARI reported a DVT event (IR=0.3) and 32 (0.8%) patients reported a PE event (IR=0.2).6,7

    Of the 60 patients with a VTE event, 42 (1.1%) were reported it as SAEs (IR=0.3). The VTE events reported as SAEs included

    • 29 PEs (IR=0.2), 2 of which resulted in death, and 
    • 22 DVTs (IR=0.2).

    One patient in the active comparator MTX treatment arm had a fatal PE event.5

    Statistical analysis did not reveal an association between

    • timing of the VTE relative to initial BARI exposure2
    • VTE in relation to BARI exposure based on administered dose5,7
    • VTE in relation to treatment duration,7 or
    • VTE relative to platelet counts at baseline, postbaseline and the change from baseline to week 2.4

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

    • history of VTE
    • older age
    • higher BMI, and
    • use of COX-2 inhibitors at time of first BARI dose.8
    Incidence of VTE Events in the BARI RA Clinical Development Program2,5

     

    VTE

    VTE

    DVT

    DVT

    PE

    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]

    4 Study Extended Dataset (through 01 September 2019)

     

     

     

     



    Bari 2-mg (N=479)

    5 [0.6]

    3 [0.4]

    4 [0.5]

    3 [0.4]

    2 [0.3]

    1 [0.1]

    Bari 4-mg (N=479)

    4 [0.5]

    3 [0.4]

    2 [0.3]

    1 [0.1]

    2 [0.3]

    2 [0.3]

    All BARI RA Dataset (PYE=13,148, median exposure=4.2 yrs, maximum exposure=8.4 yrs)

     

     

     

     

     


    Phases 1-3 (N=3770)

    60 [0.5]

    42 [0.3]

    41 [0.3]

    22 [0.2]

    32 [0.2]

    29 [0.2]

    Abbreviations: 4MSU = 4-month safety update; BARI = baricitinib; DVT = deep vein thrombosis; EAIR = exposure-adjusted incidence rate per 100 patient years; Ext = extended; IR = incidence rate; MTX = methotrexate; NA = not available; PC = placebo-controlled; PE = pulmonary embolism; RA = rheumatoid arthritis; SAE = serious adverse event; TEAE = treatment-emergent adverse event; VTE = venous thromboembolism ; yrs = years.
    Including follow-up data where applicable. SAEs by International Conference on Harmonisation (ICH) only.

    Postmarketing Spontaneous Reports

    Based on postmarketing spontaneous reports from February 2017, after the first global approval for rheumatoid arthritis, through February 2020

    • PE was rarely reported (≥0.01% and <0.1%), and
    • DVT was rarely reported (≥0.01% and <0.1%).5

    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.5

    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.5

    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.9

    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.9

    References

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

    2Genovese 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

    3Eli 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.

    4Taylor 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

    5Data on file, Eli Lilly and Company and/or one of its subsidiaries.

    6Genovese 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

    7Genovese 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. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

    8Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 7 years: an updated integrated safety analysis. Presented as an oral presentation at: European League Against Rheumatism (EULAR) Annual Meeting; June 12-15, 2019; Madrid, Spain.

    9Goldman 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

    Glossary

    BARI = baricitinib

    BMI = body mass index

    COX-2 = cyclooxygenase-2

    DVT = deep vein thrombosis

    IR = incidence rate

    PE = pulmonary embolism

    PY(s) = patient year(s)

    PYE = patient-years of exposure

    RA = rheumatoid arthritis

    SAE = serious adverse event

    VTE = venous thromboembolism

    Datum fӧr senaste ӧversyn October 23, 2020


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