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Olumiant ® (baricitinib)
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Can Olumiant® (baricitinib) be used concomitantly with antithrombotic, antiplatelet and anticoagulant agents?
In rheumatoid arthritis (RA) clinical trials, some patients treated with baricitinib were taking concomitant antithrombotic therapy, including antiplatelet and anticoagulant medications.
Content Overview
Description of Baricitinib Rheumatoid Arthritis Phase 3 Clinical Trials
Potential for Drug-Drug Interactions Based on Pharmacology/Pharmacokinetics Studies
- Antithrombotic, Antiplatelet and Anticoagulant Treatments
- Drug-Drug Interaction Pharmacology Studies
Concomitant Use of Antithrombotic Medications in Phase 3 Clinical Trials
Information from the label
In a retrospective observational study of baricitinib in rheumatoid arthritis patients, a higher rate of venous thromboembolic events (VTE) was observed compared to patients treated with TNF inhibitors.1
In a large randomized active‑controlled study of tofacitinib (another JAK inhibitor) in rheumatoid arthritis patients 50 years and older with at least one additional cardiovascular risk factor, a dose dependent higher rate of VTE including deep venous thrombosis (DVT) and pulmonary embolism (PE) was observed with tofacitinib compared to TNF inhibitors.1
In patients with cardiovascular or malignancy risk factors, baricitinib should only be used if no suitable treatment alternatives are available.1
In patients with known VTE risk factors other than cardiovascular or malignancy risk factors, baricitinib should be used with caution.1
VTE risk factors other than cardiovascular or malignancy risk factors include1
- previous VTE,
- patients undergoing major surgery,
- immobilisation,
- use of combined hormonal contraceptives or hormone replacement therapy, and
- inherited coagulation disorder.
Patients should be re‑evaluated periodically during baricitinib treatment to assess for changes in VTE risk.1
Promptly evaluate patients with signs and symptoms of VTE and discontinue baricitinib in patients with suspected VTE, regardless of dose or indication.1
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).2
- RA-BEAM compared baricitinib 4 mg vs placebo or adalimumab, with background MTX, in patients with inadequate response to MTX.3
- 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.4
- 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.5
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.1
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.
- For data on patients receiving concomitant aspirin in the baricitinib RA phase 3 trials, please see Concomitant Aspirin Use in Baricitinib Rheumatoid Arthritis Phase 3 Clinical Trials.7
|
Concomitant ASA Use by ATCa, n (%) |
||
n |
Antithrombotic |
Analgesic |
|
Baricitinib 2 mg |
174 |
20 (11.5) |
0 |
Baricitinb 4 mg |
177 |
24 (13.6) |
1 (0.6) |
PBO |
176 |
21 (11.9) |
0 |
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) |
Baricitinib 4 mg |
487 |
34 (7.0) |
0 |
Adalimumab |
330 |
19 (5.8) |
1 (0.3) |
PBO |
488 |
22 (4.5) |
1 (0.2) |
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.
For data on patients receiving other non-aspirin concomitant antithrombotics, including antiplatelets and anticoagulants, please see
- Concomitant Antithrombotic Medications Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA-BEAM
- Concomitant Antithrombotic Medications Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA-BUILD
- Concomitant Antithrombotic Medications Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA-BEACON, and
- Concomitant Antithrombotic Medications Other Than Aspirin Administered for Rheumatoid Arthritis in Study RA-BEGIN.
ATC Level 2 Term (Preferred Name) |
Placebo (N=488) |
Baricitinib 4 mg (N=487) |
ADA (N=330) |
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.
Note: The overall category of antithrombotic medications includes antiplatelet and anticoagulant medications.
ATC Level 2 Term (Preferred Name) |
Placebo (N=228) |
Baricitinib 2 mg (N=229) |
Baricitinib 4 mg (N=227) |
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.
Note: The overall category of antithrombotic medications includes antiplatelet and anticoagulant medications.
ATC Level 2 Term (Preferred Name) |
Placebo (N=176) |
Baricitinib 2 mg (N=174) |
Baricitinib 4 mg (N=177) |
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.
ATC Level 2 Term (Preferred Name) |
MTX (N=210) |
Baricitinib 4 mg (N=159) |
Baricitinib 4 mg + MTX (N=215) |
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; 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
References
1Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2Fleischmann 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
3Taylor 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
4Dougados 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
5Genovese 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
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