Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Malignitet och lymfoproliferativ sjukdom

Maligniteter har observerats i baricitinibs kliniska prövningsprogram för RA.

Malignancy and Lymphoproliferative Disorders in Rheumatoid Arthritis Clinical Trials

Safety Dataset Descriptions

Analyses were conducted using integrated safety datasets described in Table 1.

Table 1. Integrated Analysis Datasets Used to Evaluate Safety in Rheumatoid Arthritis Clinical Trials1-3

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 is 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).

4-Study Extended Dataset

Studies: JADA, JADN, RA-BUILD, RA-BEACON, RA-BEYOND (extension)

Compares BARI 4 mg vs BARI 2 mg including extended evaluations

Includes patients with RA from 2 phase 2 and 2 phase 3 studies and any further exposure for those patients in the phase 3 extension study, RA-BEYOND, who were randomized to

  • BARI 4 mg (N=479, PYE=781.1, median exposure=342 days, maximum exposure=3085 days), or

  • BARI 2 mg (N=479, PYE=774.9, median exposure=257 days, maximum exposure=2370 days).

Evaluation time period included randomization through last available observation incorporating extension data through 01 September 2019 unless otherwise specified.

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=13,148, median exposure=4.2 yrs, maximum exposure=8.4 yrs) from 1 phase 1, 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=3400)

  • BARI 2 mg (n=1077), 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 through 01 September 2019 unless otherwise specified.

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

a Patients 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.

Malignancies Excluding Non-Melanoma Skin Cancers in RA Clinical Trials

The IRs and 95% CIs for malignancies excluding NMSC in each integrated dataset, as well as individual comparator studies, RA-BEAM and RA-BEGIN, are provided in Figure 1.

Figure 1. Incidence Rate and 95% CI by Analysis Dataset for Malignancies Excluding Non-Melanoma Skin Cancer in RA Clinical Trials2-4

Abbreviations: ADA = adalimumab; BARI = baricitinib; DMARD = disease-modifying antirheumatic drug; IR = inadequate responder; Mono = monotherapy; MTX = methotrexate; PBO = placebo; pts = patients; PYE = patient-years of exposure; RA = rheumatoid arthritis.

7-Study Placebo-Controlled Dataset

Through 24 weeks of treatment, the IR per 100 PY for malignancy excluding NMSC was

  • 0.4 (n=2) in the BARI 4-mg group (N=1142)

  • 0.5 (n=1) in the BARI 2-mg group (N=479), and

  • 0.4 (n=2) in the placebo group (N=1215).2

4-Study Extended Dataset

The IRs per 100 PYs for malignancies excluding NMSC across additional analyses in the 4-study extended dataset, were

  • 1.4 in the BARI 4-mg group compared with 0.6 in the BARI 2-mg group for the “as-treated” analysis, and

  • 1.0 in the BARI 4-mg group and 1.1 in the BARI 2-mg group for the “as-randomized” analysis.3

All BARI RA Dataset

In the All BARI RA dataset, 122 patients reported a malignancy excluding NMSC representing an IR of 0.9 per 100 PYs.4

The IRs remained stable in the All BARI RA dataset with prolonged treatment.4 See details including age-adjusted incidence rates in Figure 2

Figure 2. Incidence Rate Over Time of Malignancies Excluding Non-Melanoma Skin Cancer in Rheumatoid Arthritis Clinical Trials4

Abbreviations: BARI = baricitinib; IR = incidence rate; PYE = patient-years of exposure; RA = rheumatoid arthritis; WHO = World Health Organization; wks = weeks.

a IRs were standardized to the WHO world population 2000-2025 using 5-year age increments within each reported 48-week time period to account for aging of the All-BARI-RA cohort over the 6 years of the reported data.

Lymphoma in RA Clinical Trials

There were no cases of lymphoma reported for patients administered BARI in the randomized, controlled periods of the RA clinical program.2

In the All BARI RA dataset, lymphoma was reported in 8 patients during the long-term extension study (IR 0.1 per 100 PY) including

  • 2 patients who initiated treatment with BARI 4 mg

  • 1 patient who initially received adalimumab then switched to BARI 4 mg, and

  • 5 patients who initially received placebo were then switched or rescued to BARI 4 mg.3,4

Lymphoproliferative Disorders in RA Clinical Trials

In the All BARI RA dataset with data from 3770, a total of 10,127 PYE, and up to 6.9 years maximum exposure, 4 cases of lymphoproliferative disorder were reported including

  • 1 patient diagnosed 259 days after initiation of BARI 4 mg

  • 1 patient diagnosed 112 days after rescue to BARI 4 mg from initial treatment with adalimumab

  • 1 patient diagnosed 638 days after initiation of BARI 4 mg, and

  • 1 patient diagnosed 695 days after switching to BARI 4 mg from initial treatment with adalimumab.3,5

Non-Melanoma Skin Cancers in RA Clinical Trials

7-Study Placebo-Controlled Dataset

Through 24 weeks of assigned treatment, the IR per 100 PY for NMSC was

  • 0.6 (n=3) in the BARI 4-mg group (N=1142)

  • 0.0 in the BARI 2-mg group (N=479), and

  • 0.2 (n=1) in the placebo group (N=1215).2

4-Study Extended Dataset

The IRs per 100 PYs for NMSC, with "as-treated" data, were 1.2 for BARI 4 mg compared with 0.3 for BARI 2 mg.3

All BARI RA Dataset

In the All BARI RA dataset, there were 44 reported cases of NMSC representing an IR of 0.33 per 100 PYs.1

Information from the label

The risk of malignancies including lymphoma is increased in patients with rheumatoid arthritis. Immunomodulatory medicinal products may increase the risk of malignancies including lymphoma. The clinical data are insufficient to assess the potential incidence of malignancies following exposure to baricitinib. Long-term safety evaluations are ongoing.6

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.6

References

1. 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

2. 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

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

4. 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.

5. Smolen JS, Genovese MC, Takeuchi T, et al. Safety profile of baricitinib in patients with active rheumatoid arthritis with over 2 years median time in treatment [published online September 15, 2018]. J Rheumatol. https://dx.doi.org/10.3899/jrheum.171361

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

Glossary

BARI = baricitinib

IR = incidence rate

NMSC = nonmelanoma skin cancer

PY(s) = patient year(s)

PYE = patient-years of exposure

RA = rheumatoid arthritis

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 M08 03


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