Olumiant ® (baricitinib)

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What was the incidence of gastrointestinal adverse events in the Olumiant® (baricitinib) rheumatoid arthritis clinical development program?

Gastrointestinal adverse events reported by at least 2% of patients taking baricitinib in the placebo-controlled clinical trials included abdominal pain, constipation, diarrhea, nausea, upper abdominal pain, and vomiting.

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Gastrointestinal Adverse Events Observed in Rheumatoid Arthritis Clinical Trials

The integrated datasets used to evaluate gastrointestinal (GI) adverse events (AEs) in patients with rheumatoid arthritis (RA) are described in more detail in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials. The exposure information, including median, maximum, and total patient-years of exposure (PYE), described in the table is applicable to the data presented below unless otherwise specified.

Exposure-adjusted incidence rates (EAIRs) were calculated as the number of patients with an event per 100 PYE time, with exposure not censored at time of event.1

Incidence of Treatment-Emergent Gastrointestinal Adverse Events Related to Tolerability

Based on data from clinical studies for baricitinib, nausea and abdominal pain are listed as common (≥1% and <10%) adverse drug reactions.2

7-Study Placebo-Controlled Dataset

Through 24 weeks, GI events reported by at least 2% of patients in either the baricitinib 4-mg group or baricitinib 2-mg group were

Gastrointestinal Disorders System Organ Class Treatment-Emergent Adverse Events Through Week 24 From the 7-Study Placebo-Controlled Dataset2

 

Treatment Groupsa

Events, n (%) [EAIR]

PBO + csDMARDs

(N=1215)

BARI 2 mg + csDMARDs

(N=479)

BARI 4 mg + csDMARDs

(N=1142)

Gastrointestinal disorders

160 (13.2) [35.5]

94 (19.6) [50.6]

184 (16.1) [39.0]

Nausea

20 (1.6) [4.4]

14 (2.9) [7.5]

32 (2.8) [6.8]

Diarrhea

41 (3.4) [9.1]

21 (4.4) [11.3]

28 (2.5) [5.9]

Abdominal pain

12 (1.0) [2.7]

11 (2.3) [5.9]

10 (0.9) [2.1]

Upper abdominal pain

7 (0.6) [1.6]

12 (2.5) [6.5]

19 (1.7) [4.0]

Lower abdominal pain

1 (0.1) [0.2]

0

0

Constipation

15 (1.2) [3.3]

10 (2.1) [5.4]

16 (1.4) [3.4]

Dyspepsia

11 (0.9) [2.4]

2 (0.4) [1.1]

17 (1.5) [3.6]

Vomiting

10 (0.8) [2.2]

12 (2.5) [6.5]

16 (1.4) [3.4]

Gastritis

5 (0.4) [1.1]

3 (0.6) [1.6]

11 (1.0) [2.3]

Mouth ulceration

4 (0.3) [0.9]

6 (1.3) [3.2]

4 (0.4) [0.8]

Gastroesophageal reflux disease

11 (0.9) [2.4]

5 (1.0) [2.7]

8 (0.7) [1.7]

Abbreviations: BARI = baricitinib; csDMARDs = conventional synthetic disease-modifying antirheumatic drugs; EAIR = exposure-adjusted incidence rate; MedDRA = Medical Dictionary for Regulatory Activities; PBO = placebo.
Note: To assist in interpretation, event rates, adjusted for patient-years of exposure, are provided to take into account the different drug exposure times.

aTreatment-emergent adverse events reported by MedDRA preferred term during the placebo-controlled period up to week 24, with data up to rescue. Events were included if reported in ≥1.0% of patients in the BARI 4-mg group.

In the 7-study integrated analysis dataset, a significantly higher (p<.05) proportion of patients in the baricitinib 4-mg group (1.7%) than in the placebo group (0.6%) reported a treatment-emergent adverse event (TEAE) of upper abdominal pain.2

In a similar dataset comparing baricitinib 4 mg with placebo through 16 weeks of treatment, approximately 50% of nausea events occurred within the first 14 days of treatment.2

All Baricitinib Rheumatoid Arthritis Dataset

Incidence of Treatment-Emergent Nausea

In patients with RA who received baricitinib in clinical trials with maximum exposure of 9.3 years, treatment-emergent nausea was reported in 210 (5.6%) patients with an EAIR of 1.4.3

Of the 210 reported TEAEs of nausea

  • none of these events were considered serious
  • 7 events led to temporary interruptions of baricitinib, and
  • 1 led to permanent discontinuation of baricitinib.2

Incidence of Treatment-Emergent Abdominal Pain

In patients with RA who received baricitinib in clinical trials, treatment-emergent abdominal pain was reported in 108 (2.9%) patients. The incidence of abdominal pain, and those classified as serious adverse events (SAEs) or those that led to treatment interruption or permanent discontinuation of baricitinib can be seen in Incidence of Treatment-Emergent Abdominal Pain in the All-BARI-RA Dataset.2

    Incidence of Treatment-Emergent Abdominal Pain in the All-BARI-RA Dataset2

     

    Incidence, n (%) [EAIR]

    Serious AE, n

    Led to Temporary Interruption, n

    Led to Permanent Discontinuation, n

    Abdominal pain

    108 (2.9) [0.71]

    3

    11

    3

    Upper abdominal pain

    120 (3.2) [0.79]

    2

    8

    1

    Lower abdominal pain

    12 (0.3) [0.08]

    0

    1

    0

    Abbreviations: AE = adverse event; BARI = baricitinib; EAIR = exposure-adjusted incidence rate; RA = rheumatoid arthritis.

    Treatment-Emergent Adverse Events of Gastrointestinal Perforations

    Gastrointestinal Perforations in Patients With Rheumatoid Arthritis

    Gastrointestinal perforation is a serious but rare AE that has been observed in patients with RA.4,5 Known risk factors for GI perforation include

    • the use of glucocorticoids or nonsteroidal anti-inflammatory drugs (NSAIDs)
    • diverticular disorder
    • increased age, and
    • higher levels of comorbidity.6

    In a large claims database study of patients with RA, regardless of treatment, the observed GI perforation rate was 1.7 per 1000 patient years.6

    Gastrointestinal perforation is a potential risk with certain RA therapies that interrupt interleukin-6 signaling.7,8

    Identification of GI perforation events in the baricitinib RA clinical program was based on events identified from the GI perforation standardized Medical Dictionary for Regulatory Activities (MedDRA) term, and were considered definite or probable perforation after internal medical review.2 The integrated analysis datasets used to evaluate GI perforation are described in more detail in Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials.

    All Baricitinib Rheumatoid Arthritis Dataset

    In the All-BARI-RA dataset, 9 patients treated with baricitinib had a confirmed GI perforation event after the randomized controlled period. The incidence rate (95% CI) in the All-BARI-RA dataset was 0.06 (95% CI, 0.03-0.11).9

    The cases of GI perforation included

    • upper GI perforations
      • 1 case of a gastric ulcer perforation
      • 1 case of intestinal perforation
    • lower GI perforations
      • 3 cases of diverticular perforation
      • 1 case of abscess intestinal
      • 1 case of appendicitis perforated
      • 1 case of intestinal perforation, and
      • 1 case of peritonitis.2

    All of these events with the exception of 1 case of intestinal perforation were SAEs. Permanent discontinuation occurred in 1 patient each with diverticular perforation, peritonitis, and gastric ulcer perforation. There were no deaths due to GI perforations.2

    The incidence of GI perforation by dose was not significantly different between patients ever on baricitinib 2 mg and ever on baricitinib 4 mg (Summary of Gastrointestinal Perforations by Dose in the All-BARI-RA Dataset).2

    Summary of Gastrointestinal Perforations by Dose in the All-BARI-RA Dataset2

     

    Ever on BARI 2 mg
    N=1077
    n (EAIR) [95% CI]

    Ever on BARI 4 mg
    N=3401
    n (EAIR) [95% CI]

    GI perforations

    3 (0.11) [0.02, 0.33]

    6 (0.05) [0.02, 0.11]

    Abbreviations: BARI = baricitinib; EAIR = exposure-adjusted incidence rate; GI = gastrointestinal; RA = rheumatoid arthritis.

    Diverticulitis as a Risk Factor for Gastrointestinal Perforation

    In the All-BARI-RA dataset,

    • 23 patients (0.6%; 0.15 EAIR) had a reported TEAE of diverticulitis, and
    • 3 patients (0.1%; 0.02 EAIR) had a reported SAE of diverticular perforation.2

    Of the 23 reported cases of diverticulitis,

    • 12 were SAEs
    • 6 led to temporary interruption of baricitinib treatment, and
    • 1 led to permanent discontinuation of baricitinib treatment.2

    The TEAEs of diverticulitis occurred in patients with existing risk factors including preexisting diverticular disorder, older age, overweight and obesity, and chronic corticosteroid or NSAID treatment.3

    Information From the Label

    Cases of diverticulitis and gastrointestinal perforation have been reported in clinical trials and from postmarketing sources.10

    Baricitinib should be used with caution in patients with diverticular disease and especially in patients chronically treated with concomitant medicinal products associated with an increased risk of diverticulitis: nonsteroidal anti-inflammatory drugs, corticosteroids, and opioids.10

    Patients presenting with new onset abdominal signs and symptoms should be evaluated promptly for early identification of diverticulitis or gastrointestinal perforation.10

    Nausea, abdominal pain and diverticulitis are a known side effects of baricitinib, the reported frequency is common (≥ 1/100 to < 1/10) for nausea and abdominal pain and uncommon (≥ 1/1 000 to < 1/100) for diverticulitis.10

    In rheumatoid arthritis clinical studies, in treatment-naïve patients, through 52 weeks, the frequency of nausea10

    • was greater for the combination treatment of methotrexate and baricitinib (9.3 %) compared to
    • methotrexate alone (6.2 %) or
    • baricitinib alone (4.4 %).10

    Cases or abdominal pain were usually mild, transient, not associated with infectious or inflammatory gastrointestinal disorders, and did not lead to treatment interruption.10

    References

    1Genovese 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

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

    3Taylor 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

    4Curtis JR, Xie F, Chen L, et al. The incidence of gastrointestinal perforations among rheumatoid arthritis patients. Arthritis Rheumatol. 2011;63(2):346-351. http://dx.doi.org/10.1002/art.30107

    5Závada J, Lunt M, Davies R, et al; British Society for Rheumatology Biologics Register (BSRBR) Control Centre Consortium. The risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the BSRBR-RA. Ann Rheum Dis. 2014;73(1):252-255. http://dx.doi.org/10.1136/annrheumdis-2012-203102

    6Curtis JR, Lanas A, John A, et al. Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012;64(12):1819-1828. http://dx.doi.org/10.1002/acr.21764

    7DO NOT USE -- xXeljanz [xpackage insert]. New York, NY: xPfizer, Inc; 2018.

    8Actemra [package insert]. South San Francisco, CA: Genentech, Inc; 2018.

    9Taylor 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. Published online October 27, 2021. https://doi.org/10.1136/annrheumdis-2021-221276

    10Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

    11Genovese 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):642-643. European League Against Rheumatism abstract FRI0123. https://ard.bmj.com/content/79/Suppl_1/642.1

    Appendix

    Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials1-3,11

    Analysis Set

    Descriptiona

    7-Study Placebo-Controlled Dataset

    Studies: JADC, JADA, JADN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE

    Compares BARI 4 mg vs placebo

    Includes patients with RA from 3 phase 2 and 4 phase 3 studies who were randomized to

    • BARI 4 mg (N=1142 [exposure through 24 weeks: PYE=471.8, median exposure=169 days, maximum exposure=211 days]), or
    • placebo (N=1215 [exposure through 24 weeks: PYE=450.8, median exposure=166 days, maximum exposure=235 days]).

    Patients in the placebo group could have been taking

    • background MTX, or
    • in some studies, other conventional DMARD therapy.

    Evaluation time periods included

    • 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.

    BARI 2-mg Analysis Set

    BARI 2-mg data are derived from 4 studies in which both BARI 2 mg (N=479 [exposure through 24 weeks: PYE=185.8, median exposure=168 days, maximum exposure=197 days]) and BARI 4 mg were options during randomization (JADA, JADN, RA-BUILD, RA-BEACON).

    All-BARI-RA Dataset

    Studies: JADB, JADC, JADA, JADN, RA-BEGIN, RA-BEAM, RA-BUILD, RA-BEACON, RA-BALANCE, RA-BEYOND (extension)

    No between-group comparisons

    Includes patients with RA (N=3770; PYE=14,744 PY exposure to BARI and 15,114 PY overall observation including time on BARI and follow up; median exposure=4.6 years; maximum exposure=9.3 years) from 1 phase 1b, 3 phase 2, 5 phase 3 studies, and 1 phase 3 extension study who received BARI at a variety of doses, including

    • BARI 4 mg (n=3401, PYE=11,872)
    • BARI 2 mg (n=1077, PYE=2678), and
    • BARI 1 mg, 7 mg, 8 mg, and 10 mg QD doses not evaluated in confirmatory studies.

    Patients had to have received at least 1 dose of BARI and could have received different doses throughout the trials.

    Evaluation time period is all exposure time points including after rescue or changes in study drug unless otherwise specified.

    Abbreviations: BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; MTX = methotrexate; PY = patient-years; PYE = patient-years of exposure; QD = once daily; RA = rheumatoid arthritis.

    aPatients with renal function impairment who were randomized to BARI 4 mg, but treated with the 2-mg dose were analyzed in the BARI 4-mg group.

    Date of Last Review: 01 December 2021


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