Olumiant ® (baricitinib)

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Olumiant® (baricitinib): Concomitant Use With Antithrombotic Agents

In rheumatoid arthritis (RA) clinical trials, some patients treated with baricitinib were taking concomitant antithrombotic therapy, including antiplatelet and anticoagulant medications.

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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-BEGIN compared baricitinib 4 mg monotherapy, baricitinib 4 mg plus methotrexate (MTX), and MTX monotherapy in patients who had limited or no prior treatment with MTX and were naïve to other disease-modifying antirheumatic drugs (DMARDs).1
  • RA-BEAM compared baricitinib 4 mg vs placebo or adalimumab, with background MTX, in patients with inadequate response to MTX.2 
  • RA-BUILD compared baricitinib 2 mg and 4 mg vs placebo, with background conventional synthetic DMARD (csDMARD) therapy, in patients with inadequate response to csDMARDs.3
  • RA-BEACON compared baricitinib 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with an inadequate response to at least one TNF inhibitor, who may also have had an inadequate response to one or more non-TNF inhibitor biologic 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

Potential for Drug-Drug Interactions Based on Pharmacology/Pharmacokinetics Studies

Antithrombotic, Antiplatelet and Anticoagulant Treatments

Concomitant use of antithrombotic treatments are not included in the drug-drug interaction information specific to baricitinib (BARI), and drug-drug interaction studies were not performed specifically for BARI and any anticoagulant or antiplatelet agents.6

Drug-Drug Interaction Pharmacology Studies

There were no clinically relevant effects on baricitinib pharmacokinetics (PK) when baricitinib was coadministered with

  • a cytochrome P450 (CYP) 3A inhibitor (ketoconazole)
  • a CYP2C19/CYP2C9/CYP3A inhibitor (fluconazole)
  • a CYP3A inducer (rifampicin)
  • a P-glycoprotein (Pgp) inhibitor (cyclosporine), or
  • MTX.6

Concomitant Use of Antithrombotic Medications in Phase 3 Clinical Trials

Concomitant use of antithrombotic medications, which included antiplatelet and anticoagulant treatments, was not prohibited in the phase 3 clinical studies.7

Patients with a medical history of venous thromboembolism (VTE) were not specifically excluded from the phase 3 trials.7

Baseline Use of Antithrombotics, Antiplatelets and Anticoagulants

Patient baseline use of antithrombotic medications, which includes both antiplatelet and anticoagulant medications, but not dose amount, was captured in the clinical trials as part of concomitant medications.

Aspirin accounted for the majority of antithrombotic agents used at baseline.

Concomitant Aspirin Use in Baricitinib Rheumatoid Arthritis Phase 3 Clinical Trials7


Study

Concomitant ASA Use by ATCa, n (%)

n

Antithrombotic

Analgesic

RA-BEACON4,b (N=527)

Baricitinib 2 mg

174

20 (11.5)

0

Baricitinb 4 mg

177

24 (13.6)

1 (0.6)

PBO

176

21 (11.9)

0

RA-BUILDc,3 (N=684)

Baricitinib 2 mg

229

19 (8.3)

1 (0.4)

Baricitinib 4 mg

227

20 (8.8)

1 (0.4)

PBO

228

16 (7.0)

1 (0.4)

RA-BEAMd,2 (N=1305)

Baricitinib 4 mg

487

34 (7.0)

0

Adalimumab

330

19 (5.8)

1 (0.3)

PBO

488

22 (4.5)

1 (0.2)

RA-BEGINe,1 (N=584)

Baricitinib 4 mg

159

13 (8.2)

1 (0.6)

Baricitinib 4 mg + MTX

215

11 (5.1)

0

MTX

210

10 (4.8)

0

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

aDose or dose range was not collected.

bRA-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.

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

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

eRA-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.

Concomitant Antithrombotic Therapies Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA BEAM7

ATC Level 2 Term (Preferred Name)

Placebo (N=488)
n (%)

BARI 4 mg (N=487)
n (%)

ADA (N=330)
n (%)

Antithrombotic Agents

35 (7.2)

47 (9.7)

28 (8.5)

Warfarin

4 (0.8)

6 (1.2)

0

Enoxaparin

4 (0.8)

4 (0.8)

2 (0.6)

Clopidogrel

3 (0.6)

3 (0.6)

3 (0.9)

Nadroparin

0

2 (0.4)

0

Rivaroxaban

0

2 (0.4)

0

Acenocoumarol

1 (0.2)

1 (0.2)

2 (0.6)

Dipyridamole

0

1 (0.2)

0

Heparin

2 (0.4)

1 (0.2)

0

Prasugrel

0

1 (0.2)

0

Sulodexide

0

1 (0.2)

1 (0.3)

Ticagrelor

0

1 (0.2)

0

Tinzaparin

0

1 (0.2)

0

Cilostazol

1 (0.2)

0

0

Dalteparin

0

0

1 (0.3)

Heparinoid

0

0

1 (0.3)

Magnyl

0

0

1 (0.3)

Paynocil

0

0

1 (0.3)

Streptokinase

0

0

1 (0.3)

Ticlopidine

0

0

1 (0.3)

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

Note: The overall category of antithrombotic medications includes antiplatelet and anticoagulant medications.

Concomitant Antithrombotic Therapies Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA-BUILD7

ATC Level 2 Term (Preferred Name)

Placebo (N=228)
n (%)

BARI 2 mg (N=229)
n (%)

BARI 4 mg (N=227)
n (%)

Antithrombotic Agents

23 (10.1)

25 (10.9)

26 (11.5)

Cilostazol

0

0

1 (0.4)

Clopidogrel

2 (0.9)

1 (0.4)

1 (0.4)

Enoxaparin

5 (2.2)

0

1 (0.4)

Heparinoid

0 

0

1 (0.4)

Mesoglycan

0

0

1 (0.4)

Rivaroxaban

0

0

1 (0.4)

Warfarin

0

2 (0.9)

1 (0.4)

Acenocoumarol

1 (0.4)

0

0

Fondaparinux

0

1 (0.4)

0

Magnyl

0

2 (0.9)

0

Phenprocoumon

1 (0.4)

0

0

Ticagrelor

1 (0.4)

0

0

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

Note: The overall category of antithrombotic medications includes antiplatelet and anticoagulant medications.

Concomitant Antithrombotic Medications Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA-BEACON7

ATC Level 2 Term (Preferred Name)

Placebo (N=176)
n (%)

Baricitinib 2 mg (N=174)
n (%)

Baricitinib 4 mg (N=177)
n (%)

Antithrombotic Agents

30 (17.0)

25 (14.4)

33 (18.6)

Clopidogrel

6 (3.4)

2 (1.1)

6 (3.4)

Warfarin

5 (2.8)

2 (1.1)

5 (2.8)

Phenprocoumon

0

1 (0.6)

2 (1.1)

Enoxaparin

1 (0.6)

2 (1.1)

1 (0.6)

Fondaparinux

0

0

1 (0.6)

Heparin

1 (0.6)

0

1 (0.6)

Acenocoumarol

0

1 (0.6)

0

Certoparin Sodium

0

1 (0.6)

0

Dabigatran

2 (1.1)

1 (0.6)

0

Dalteparin

0

1 (0.6)

0

Prasugrel

1 (0.6)

0

0

Abbreviation: ATC = Anatomical Therapeutic Chemical classification system.

Note: The overall category of antithrombotic medications includes antiplatelet and anticoagulant medications.

Concomitant Antithrombotic Therapies Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA BEGIN7

ATC Level 2 Term (Preferred Name)

MTX (N=210)
n (%)

BARI 4 mg (N=159)
n (%)

BARI 4 mg + MTX (N=215)
n (%)

Antithrombotic Agents

15 (7.1)

15 (9.4)

14 (6.5)

Enoxaparin

1 (0.5)

0

3 (1.4)

Rivaroxaban

0

0

2 (0.9)

Acenocoumarol

0

0

1 (0.5)

Alteplase

0

0

1 (0.5)

Clopidogrel

1 (0.5)

2 (1.3)

1 (0.5)

Heparin

2 (1.0)

1 (0.6)

1 (0.5)

Warfarin

0

0

1 (0.5

Magnyl

0

1 (0.6)

0

Phenprocoumon

1 (0.5)

0

0

Ticagrelor

0

1 (0.6)

0

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

Note: The overall category of antithrombotic medications includes antiplatelet and anticoagulant medications.

Association Between Antithrombotics and Antiplatelets and Risk of Venous Thromboembolism 

Incidence of Venous Thromboembolism in the Rheumatoid Arthritis Clinical Trials

The All baricitinib RA analysis set included 3770 patients with RA who received baricitinib 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 include a long-term extension study (RA-BEYOND) with

  • 14,744 PYE to baricitinib
  • 15,114 PY overall observation including time on baricitinib and follow up
  • median exposure of 4.6 years, and
  • maximum exposure of 9.3 years.8

In the ALL baricitinib RA dataset, 73 patients treated with baricitinib reported VTE events with an incidence (IR) of 0.5 per 100 patient-years at risk (PYR).8

In the ALL baricitinib RA dataset, there were

  • 52 patients with DVTs (IR=0.4), and
  • 39 patients with a PE (IR=0.3).8

Baseline Use of Antithrombotic Agents and Venous Thromboembolism

In the All baricitinib RA dataset, with data collected from an earlier data cut (through April 1, 2017)

  • concomitant use of baricitinib 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 baricitinib and antiplatelet agents was observed in
    • 0 of the 42 patients with VTE, and
    • 272 (7.9%) of the 3450 patients without VTE.7

No association has been observed between baseline use of antithrombotic or antiplatelet medications and VTE incidence.7

Information from the label

Cases of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.5

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.5

If clinical features of DVT/PE occur, treatment should be discontinued and patients should be evaluated promptly, followed by appropriate treatment.5

References

1Fleischmann 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

2Taylor 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

3Dougados 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. Ann Rheum Dis. 2017;76(9):1634. http://dx.doi.org/10.1136/annrheumdis-2016-210094corr1

4Genovese 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

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

6Payne C, Zhang X, Shahri N, et al. Evaluation of potential drug-drug interactions with baricitinib. Ann Rheum Dis. 2015;74(suppl 2):1063. European League Against Rheumatism abstract AB0492. https://doi.org/10.1136/annrheumdis-2015-eular.1627

7Data on file, Eli Lilly and Company and/or one of its subsidiaries.

8Taylor 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

Date of Last Review: 28 April 2022


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