Olumiant® ▼ (baricitinib): Concomitant Use With Antithrombotic Agents

Description of Baricitinib Rheumatoid Arthritis Phase 3 Clinical Trials

Each of the 4 phase 3 studies in the clinical program evaluated a distinct treatment population of patients with moderate-to-severe RA.

• RA-BUILD compared BARI 2 mg and 4 mg vs PBO, with background csDMARD therapy, in patients with inadequate response to csDMARDs.¹

• RA-BEACON compared BARI 2 mg and 4 mg vs PBO, with background csDMARD therapy, in patients with inadequate response to TNF inhibitors, other biologic DMARDs, or both.²

• RA-BEAM compared BARI 4 mg vs PBO or adalimumab, with background MTX, in patients with inadequate response to MTX.³

• RA-BEGIN compared BARI 4 mg monotherapy, MTX monotherapy, and BARI 4 mg plus MTX in patients who had limited or no prior treatment with MTX and were naïve to other DMARDs.⁴

The study population of DMARD-naïve patients from the RA-BEGIN study is not included in the approved label. However, the RA-BEGIN study is supportive for the target population of patients with an inadequate response to, or intolerance to, other DMARDs.⁵

Clinical Trial Program Criteria

Concomitant use of anticoagulant treatments was not prohibited in the phase 3 clinical studies.⁶ Concomitant use of anticoagulant treatments are not included in the drug-drug interaction information specific to BARI, and drug-drug interaction studies were not performed specifically for BARI and any anticoagulant therapies.⁷

Patients were excluded from the phase 3 trials if they 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.⁶

Drug-Drug Interactions

Antithrombotic Treatments

Concomitant use of antithrombotic treatments are not included in the drug-drug interaction information specific to BARI, and drug-drug interaction studies were not performed specifically for BARI and any anticoagulant or antiplatelet agents.⁷

Drug-Drug Interaction Pharmacology Studies

Based on clinical pharmacology studies, no clinically relevant effects on BARI pharmacokinetics occurred with the co-administration of BARI and

• a CYP3A inhibitor

• a CYP2C19/CYP2C9/CYP3A inhibitor

• a CYP3A inducer, or

• a Pgp inhibitor.⁷

Co-administration of BARI with either a CYP3A substrate or a Pgp substrate resulted in no clinically relevant effects on the pharmacokinetics of these drugs.⁷

Thrombosis Risk

Baseline Use of Antithrombotics and Antiplatelets and Association of VTE

Patient baseline use of antithrombotics, but not dose amount, was captured in the clinical trials as part of concomitant medications. Antithrombotics include aspirin and other antiplatelet agents. Aspirin accounted for the majority of antiplatelet agents used at baseline.⁶

For data on patients receiving concomitant aspirin in the BARI RA phase 3 trials, please see Table 1.

For data on patients receiving concomitant antithrombotics, please see

• Table 2

• Table 3

• Table 4, and

• Table 5.

VTE Risk Factor Analysis

Through 13 February 2018, 49 patients reported VTE events with an IR of 0.5 per 100 PY of observation time.

• Thirty-five patients reported a DVT event (IR=0.4) and 24 patients reported a PE event (IR=0.2).⁸

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.⁹

These are among reported conventional risk factors for VTE for the general population.^10,11

In data collected through April 1, 2017,

• concomitant use of BARI and antithrombotic agents was observed in

  • 3 (7.1%) of the 42 patients with VTE, and

  • 300 (8.7%) of the 3450 patients without VTE, and

• concomitant use of BARI and antiplatelet agents was observed in

  • 0 of the 42 patients with VTE, and

  • 272 (7.9%) of the 3450 patients without VTE.⁶

No association has been observed between baseline use of antithrombotic or antiplatelet medications and VTE incidence.⁶

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.⁵

DVT and PE are listed as uncommon in the table of adverse reactions in the summary of product characteristics. ⁵

Management of Patients Reporting a VTE

Of the 42 BARI-treated patients reporting a VTE through 1 April 2017, 28 patients had exposure to BARI after the event, duration ranging from 7 days to 30 months; 22 patients had at least 6 months of exposure to BARI after the event.¹²

Of the 28 patients exposed to BARI after the VTE event,

• 25 were put on continuous anti-coagulation therapy and 3 were not, and

• 2 reported an additional event, 1 and 2 years later with new risk factors, which included surgery and discontinuation of warfarin.¹²

For 12 patients, the VTE was reported after they had already discontinued BARI. Five patients reporting a VTE permanently discontinued BARI treatment (IR=0.06).¹³

Appendix

Table 1. Concomitant Aspirin Use in Baricitinib Rheumatoid Arthritis Phase 3 Clinical Trials⁶

Abbreviations: ASA = acetylsalicylic acid; ATC = Anatomical Therapeutic Chemical classification system; BARI = baricitinib; MTX = methotrexate; PBO = placebo; RA = rheumatoid arthritis.

^a Dose or dose range was not collected.

^b RA-BEACON compared BARI 2 mg and 4 mg vs PBO, with background csDMARD therapy, in patients with inadequate response to TNF inhibitors, other biologic DMARDs, or both.

^c RA-BUILD compared BARI 2 mg and 4 mg vs PBO, with background csDMARD therapy, in patients with inadequate response to cDMARDs.

^d RA-BEAM compared BARI 4 mg vs PBO or adalimumab, with background MTX, in patients with inadequate response to MTX.

^e RA-BEGIN compared BARI 4 mg monotherapy, MTX monotherapy, and BARI 4 mg plus MTX in patients who had limited or no prior treatment with MTX and were naïve to other DMARDs.

Table 2. Concomitant Antithrombotic Therapies Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA-BUILD⁶

Abbreviations: ATC = Anatomical Therapeutic Chemical classification system; BARI = baricitinib.

Table 3. Concomitant Antithrombotic Therapies Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA-BEACON⁶

Abbreviation: ATC = Anatomical Therapeutic Chemical classification system; BARI = baricitinib.

Table 4. Concomitant Antithrombotic Therapies Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA BEAM⁶

Abbreviations: ADA = adalimumab; ATC = Anatomical Therapeutic Chemical classification system; BARI = baricitinib.

Table 5. Concomitant Antithrombotic Therapies Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA BEGIN⁶

Abbreviations: ATC = Anatomical Therapeutic Chemical classification system; BARI = baricitinib; MTX = methotrexate.

References

1. Dougados 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 [published correction appears in Ann Rheum Dis. 2017;76(9):1634. http://dx.doi.org/10.1136/annrheumdis-2016-210094corr1 ]. Ann Rheum Dis. 2017;76(1):88-95. http://dx.doi.org/10.1136/annrheumdis-2016-210094

2. Genovese 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

3. Taylor 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

4. Fleischmann 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

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

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

7. Payne C, Zhang X, Shahri N, et al. Evaluation of Potential Drug-Drug Interactions With Baricitinib. Poster presented at: the Annual Meeting of the American Association of Pharmaceutical Scientists (AAPS); October 25-29, 2015; Orlando, FL.

8. 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

9. Weinblatt M, Taylor PC, Burmester GR, et al. Cardiovascular Safety – Update from up to 6 Years of Treatment with Baricitinib in Rheumatoid Arthritis Clinical Trials [abstract]. Arthritis Rheumatol. 2018;70(suppl 10):2815. https://acrabstracts.org/abstract/cardiovascular-safety-update-from-up-to-6-years-of-treatment-with-baricitinib-in-rheumatoid-arthritis-clinical-trials/

10. Wakabayashi 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

11. Ungprasert P, Srivali N, Wijarnpreecha K, et al. Non-steroidal anti-inflammatory drugs and risk of venous thromboembolism: a systematic review and meta-analysis. Rheumatology. 2015; 54(4):736-742. http://dx.doi.org/10.1093/rheumatology/keu408

12. 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

13. 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.

14. DO NOT USE - Fleischmann 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 anti-rheumatic drug treatment. Arthritis Rheumatol. 2017;69(3):506-517. http://dx.doi.org/10.1002/art.39953

▼ 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.

Glossary

BARI = baricitinib

BMI = body mass index

COX-2 = cyclooxygenase-2

CYP = cytochrome P450

csDMARD = conventional synthetic disease-modifying antirheumatic drug

DMARD = disease-modifying antirheumatic drug

DVT = deep vein thrombosis

Lilly = Eli Lilly and Company

MTX = methotrexate

PBO = placebo

PE = pulmonary embolism

Pgp = P-glycoprotein

RA = rheumatoid arthritis

VTE = venous thromboembolism