Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Incidens av lunginflammation i det kliniska utvecklingsprogrammet för reumatoid artrit

Patienter som behandlades med BARI hade ökad incidens av lunginflammation i det kliniska utvecklingsprogrammet för reumatoid artrit.

Summary

  • Pneumonia is listed as a common adverse reactions in the summary of product characteristics of Olumiant.1

  • In a 7-study placebo controlled dataset, through 24 weeks of treatment, pneumonia was reported in

    • 5 (0.4%) patients in the BARI 4-mg group,

    • 4 (0.8%) patients in the BARI 2-mg group, and

    • 5 (0.4%) patients in the placebo group.2

  • In a 4-study extended dataset, through 1 September 2019, pneumonia was reported in

    • 13 (2.7%) patients with an EAIR of 1.7

    • 7 (1.5%) patients with an EAIR of 0.9.2

  • In the All BARI RA analysis set included 3770 patients with RA who received BARI, pneumonia was reported as a TEAE in 175 (4.6%) patients with an EAIR of 1.3.2

Baricitinib and Infections

Pneumonia is listed as a common adverse reactions in the summary of product characteristics of Olumiant.1

Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo. In treatment naïve patients, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy. The risks and benefits of treatment with baricitinib should be carefully considered prior to initiating therapy in patients with active, chronic or recurrent infections.1

If an infection develops, the patient should be monitored carefully and baricitinib therapy should be temporarily interrupted if the patient is not responding to standard therapy. Baricitinib treatment should not be resumed until the infection resolves.1

Pneumonia in the Baricitinib Rheumatoid Arthritis Clinical Development Program

Exclusion Criteria in the Baricitinib 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 BARI 4 mg monotherapy, BARI 4 mg plus MTX, and MTX monotherapy in patients who had limited or no prior treatment with MTX and were naïve to other DMARDs.3

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

  • RA-BUILD compared BARI 2 mg and 4 mg vs placebo, with background csDMARD therapy, in patients with inadequate response to csDMARDs.5

  • RA-BEACON compared BARI 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.6

In the pivotal phase 3 BARI trials, RA-BEAM, RA-BEACON, RA-BUILD, and RA-BEGIN, patients were excluded if they

  • had a current or recent (less than 30 days before screening), infection with viruses, bacteria, fungi, or parasites,

  • were infected with severe infections (eg, pneumonia, cellulitis, bone or joint infection) or nontuberculous mycobacterial disease within 6 months before screening, or

  • had a history or presence of a serious and/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.2

Incidence of Pneumonia TEAEs in the Baricitinib Clinical Development Program

A TEAE is an AE that either occurred or worsened in severity after the first dose of study treatment and did not necessarily have a causal relationship to study treatment.2

7-Study Placebo-Controlled Dataset

Dataset Description

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

  • the 12-week placebo-controlled period in phase 2 studies

  • 16 weeks of assigned treatment before any opportunity for rescue therapy in phase 3 studies, and

  • 24 weeks of assigned treatment or until rescue in phase 3 studies.7

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).7

Incidence of Pneumonia

In this safety analysis, through 24 weeks of treatment, the TEAE of

  • pneumonia (MedDRA preferred term) was reported in

    • 5 (0.4%) patients in the BARI 4-mg group,

    • 4 (0.8%) patients in the BARI 2-mg group, and

    • 5 (0.4%) patients in the placebo group.2

4-Study Extended Dataset

Dataset Description

The extended dataset included patients with RA randomized to BARI 4 mg (N=479, PYE=781.1) or BARI 2 mg (N=479, PYE=774.9) 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 01 September 2019 unless otherwise specified. Data were censored at rescue or dose change.2

Incidence of Pneumonia

Table 1. Summary of the Incidence of Pneumonia in the 4-Study Extended Dataset2

n (%), [EAIR]

TEAE

TEAE

SAE

SAE

Temporary Interruptions

Temporary Interruptions

Permanent Discontinuations

Permanent Discontinuations


BARI 2 mg

BARI 4 mg

BARI 2 mg

BARI 4 mg

BARI 2 mg

BARI 4 mg

BARI 2 mg

BARI 4 mg

pneumonia

13 (2.7) [1.7]

7 (1.5) [ 0.9] 

5 (1.0) [0.65]

4 (0.8) [0.51]

6 (1.3) [0.8]

2 (0.4) [0.3]

0

1 (0.2) [0.1]

atypical pneumonia

1 (0.2) [0.1]

0

0

0

0

0

0

0

influenzal pneumonia

2 (0.4) [0.3]

0

2 (0.4) [0.26]

0

2 (0.4) [0.3]

0

0

0

viral pneumonia

1 (0.2) [0.1]

0

0

0

0

0

0

0

aspiration pneumonia

1 (0.2) [0.1]

0

1 (0.2) [0.13]

0

0

0

0

0

crypto-coccal pneumonia

NA

NA

NA

NA

NA

NA

1 (0.2) [0.1]

0

Abbreviations: BARI = baricitinib; EAIR = exposure adjusted incidence rate; NA = not applicable; SAE = serious adverse events; TEAE = treatment emergent adverse events.

All BARI RA Dataset

Dataset Description

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

  • 13,148 PYE,

  • median exposure of 4.2 years,

  • maximum exposure of 8.4 years, and

  • data through 01 September 2019.8,9

Incidence of Pneumonia

The TEAEs, SAEs, temporary interruptions, permanent discontinuations and deaths due to pneumonia in the All BARI RA dataset are presented in Table 2.

Table 2. Summary of the Incidence of Pneumonia in the All BARI RA Dataset2

n (%), [EAIR]

TEAE

SAE

Temporary Interruptions

Permanent Discontinuations

Death

pneumonia

175 (4.6) [1.3]

69 (1.8) [0.52]

75 (2.1) [0.6]

11 (0.3) [0.1]

4 (0.1) [0.03]

atypical pneumonia

7 (0.2) [0.1]

4 (0.1) [0.03]

4 (0.1) [0.0]

1 (0) [0.0]

0

bacterial pneumonia

5 (0.1) [0.0]

2 (0.1) [0.02]

3 (0.1) [0.0]

0

0

aspiration pneumonia

3 (0.1) [0.0]

3 (0.1) [0.02]

2 (0.1) [0.0]

1 (0) [0.0]

1 (0.0) [0.01]

influenzal pneumonia

4 (0.1) [0.0]

4 (0.1) [0.03]

4 (0.1) [0.0]

0

0

pneumocystis jirovecii
pneumonia

2 (0.1) [0.0]

2 (0.1) [0.02]

0

3 (0.1) [0.0]

0

viral pneumonia

2 (0.1) [0.0]

1 (0.0) [0.01]

1 (0) [0.0]

0

0

organizing pneumonia

1 (0) [0.0]

1 (0.0) [0.01]

0

1 (0) [0.0]

0

pneumonia legionella

1 (0) [0.0]

1 (0.0) [0.01]

1 (0) [0.0]

0

0

enterobacter pneumonia

1 (0) [0.0]

1 (0.0) [0.01]

1 (0) [0.0]

0

0

cryptococcal pneumonia

0

0

0

1 (0) [0.0]

0

Abbreviations: BARI = baricitinib; EAIR = exposure adjusted incidence rate; RA = rheumatoid arthritis; SAE = serious adverse events; TEAE = treatment emergent adverse events.

Postmarketing Reporting Rates Of Pneumonia

Spontaneous reporting of AEs can be highly variable and is not controlled clinical information on which to assess causality of a drug to an AE. Spontaneous reporting has limitations due to bias in reporting including incomplete information concerning the patient. When verification of product manufactured by Lilly is not obtainable, these cases are included in the spontaneous database.

From postmarketing data through 13 August 2019, the reporting rates were as follows

  • uncommonly reported (≥0.1% and <1%)

    • pneumonia

  • rarely reported (≥0.01% and <0.1%)

    • pneumocystis jirovecii pneumonia

    • bacterial pneumonia

  • very rarely reported (<0.01%)

    • atypical pneumonia

    • organising pneumonia

    • aspiration pneumonia

    • cytomegaloviral pneumonia

    • influenzal pneumonia

    • legionella pneumonia

    • pneumococcal pneumonia

    • pseudomonal pneumonia

    • staphylococcal pneumonia

    • streptococcal pneumonia, and

    • viral pneumonia.2

Reporting rates are defined according to the relative frequency with which they are reported and are described as

  • very rarely reported (<0.01%)

  • rarely reported (≥0.01% and <0.1%)

  • uncommonly reported (≥0.1% and <1%)

  • commonly reported (≥1% and <10%), and

  • very commonly reported (≥ 10%).2

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. 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

4. 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

5. 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

6. 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

7. Genovese MC, Smolen JS, Tsutomu 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

8. Genovese 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 [abstract]. Ann Rheum Dis. 2020;79(suppl 1):638. http://scientific.sparx-ip.net/archiveeular/?c=a&view=4&item=2020FRI0123

9. Genovese 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. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

Glossary

AE = adverse event

BARI = baricitinib

csDMARD = conventional synthetic disease-modifying antirheumatic drug

DMARD = disease-modifying antirheumatic drug

EAIR = exposure-adjusted incidence rate

Lilly = Eli Lilly and Company

MedDRA = Medical Dictionary for Regulatory Activities

MTX = methotrexate

PYE = patient-years of exposure

RA = rheumatoid arthritis

TEAE = treatment-emergent adverse event

TNF = tumor necrosis factor

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 2020 M06 01


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