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.

Information from the label

Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib. 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. If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.1

DVT and PE are listed as uncommon adverse event in the summary of the product characteristics of BARI. 1

Venous Thromboembolism Events in the Clinical Development Program

Venous thromboembolism events including DVT and PE have been reported in patients receiving BARI.2

Baricitinib should be used with caution in patients with RA who have risk factors for DVT or PE.2

If clinical features of DVT/PE occur, baricitinib treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.2

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 in the placebo group could have been taking background MTX or other conventional DMARDs. Evaluation time periods included through

  • 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.3,4

Data from BARI 2 mg (N=479, PYE=185.8) is 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).3,4

As shown in Table 1, 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

4-Study Extended Dataset

The extended dataset included patients with RA randomized to BARI 4 mg (N=479, PYE=698.6) or BARI 2 mg (N=479, PYE=675.6) 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 13 February 2018 unless otherwise specified. Data were censored at rescue or dose change.3,4

As shown in Table 1, in the 4 study extended dataset through 13 February 2018, no dose-response relationship was observed for VTE events. The VTE IR was

  • 0.6 for BARI 2 mg, and

  • 0.6 for BARI 4 mg.3

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, RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with

  • data through 13 February 2018, and

  • 10,127 PYE.3,4

Through 13 February 2018, as shown in Table 1, a total of 49 patients with RA reported a VTE while being treated with BARI or during post-treatment follow-up.3 Thirty-four of the DVT or PE events were reported as SAEs.2

The IR of VTE for patients in the All BARI RA dataset was 0.5 per 100 PYs of observation time through 13 February 2018.3 This IR does not appear to exceed the background rates in RA.7

  • 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 dose3

    • VTE in relation to treatment duration,3 or

    • VTE relative to platelet counts at baseline, postbaseline and the change from baseline to week 2.6

Risk factors possibly associated with VTE events were evaluated in multi-variable analysis from the ALL BARI RA dataset comparing the risks between patients with (n=49) and without events (n=3721).2

  • 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.4

Table 1. Incidence of VTE Events in the BARI RA Clinical Development Program2,3

 

 

 

 

 

 

 

 

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]

4 Study Extended Dataset (through February 13, 2018)

Bari 2-mg (N=479)

4 [0.6]

3 [0.4]

4 [0.6]

3 [0.4]

1 [0.2]

1 [0.2]

Bari 4-mg (N=479)

4 [0.6]a

3 [0.4]

2 [0.3]

1 [0.1]

2 [0.3]

2 [0.3]

All BARI RA Dataset (through February 13, 2018)

Phases 1-3 (N=3770)

49 [0.5]a

34 [0.33]a

35 [0.4]

21 [0.2]

24 [0.2]

22 [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.
Including follow-up data where applicable. SAEs by International Conference on Harmonisation (ICH) only.

a One patient inadvertently reported an SAE of DVT during the 4MSU (data cutoff of 01 January 2016). At the following interim data cutoff of 01 September 2016, a data entry error was detected, and it was revealed that the DVT event actually happened following chemotherapy for cancer which was after study discontinuation. As a result, the post-study data were removed from the database as well as from the analysis.

References

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

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

3. Genovese 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. Ann Rheum Dis. 2019;78(2):308-309. http://dx.doi.org/10.1136/annrheumdis-2019-eular.691

4. Genovese 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.

5. Eli 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.

6. Taylor 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

7. Matta F, Singala R, Yaekoub AY, Najjar R, Stein PD. Risk of venous thromboembolism with rheumatoid arthritis. Thromb Haemost. 2009; 101(1):134-138. https://doi.org/10.1160/TH08-08-0551

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

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.

Datum fӧr senaste ӧversyn 2019 M05 31


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