Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Malignitet och lymfoproliferativ sjukdom

Maligniteter har observerats i baricitinibs kliniska prövningsprogram för RA.

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.1

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.1

Malignancy

The incidence of malignancy, excluding non-melanoma skin cancer, in the BARI clinical RA program appears to be similar to the incidence reported in other RA therapeutic programs.2-7

Identification and Analysis of Malignancies

According to standard conventions, the reporting for malignancy was broken into subcategories for NMSC and malignancies excluding NMSC, each with their own set of preferred terms from the standardized MedDRA query SMQ 20000194.8

Analyses were conducted using integrated safety datasets including the

  • 7-study dataset, which evaluated patients administered BARI 4 mg, BARI 2 mg, or placebo through 24 weeks

  • All BARI RA dataset, which evaluated 3770 patients with RA from 9 randomized studies and 1 long-term extension study with data through 13 February 2018, and

  • 4-study extended dataset, which evaluated patients administered BARI 4 mg or BARI 2 mg with long-term extension data through 13 February 2018.9,10

These safety data were censored at rescue or dose change, defined as an “as-treated analysis.” The 4 study extended dataset was also evaluated without censoring for rescue or dose change, defined as an “as-randomized” analysis, to account for the long latency period of most cancers. The data in the All BARI RA dataset were not censored.9

Malignancy Excluding Non-Melanoma Skin Cancers

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).10

All BARI RA Dataset

In the All BARI RA dataset, with data through 13 February 2018, 85 patients reported a malignancy excluding NMSC representing an IR of 0.8 per 100 PYs.8,10

The IRs remained stable in the All BARI RA dataset with prolonged treatment.8,9 See details in Figure 2.

4-Study Extended Dataset

The IRs per 100 PYs for malignancies excluding NMSC across additional analyses in the 4-study extended dataset, with data through 13 February 2018, were

  • 1.4 in the BARI 4-mg group compared with 0.4 in the BARI 2-mg group for the “as-treated” analysis, and

  • 1.0 in the BARI 4-mg group and 0.8 in the BARI 2-mg group for the “as-randomized” analysis.10

Lymphoma

There were no cases of lymphoma reported for patients administered BARI in the randomized, controlled periods of the RA clinical program.7

In the All BARI RA dataset, with data through 13 February 2018, 8 cases of lymphoma were reported 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.7-10

Background methotrexate was administered in 7 out the 8 patients, and the other patient received concomitant tacrolimus.7,8

The mean time from the first dose of BARI 4 mg to diagnosis of lymphoma was 634 days (range, 342-1093 days).8

Lymphoproliferative Disorders

Four 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.7,8

Non-Melanoma Skin Cancers

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).10

All BARI RA Dataset

In the All BARI RA dataset, with data through 13 February 2018, there were 37 reported cases of NMSC representing an IR of 0.4 per 100 PYs.10

4-Study Extended Dataset

The IRs per 100 PY for NMSC, with "as-treated" data through 13 February 2018, were 1.1 for BARI 4 mg compared with 0.3 for BARI 2 mg.10

Pharmacovigilance

Appropriate pharmacovigilance, including analysis of ongoing and planned clinical studies, observational postmarketing safety studies, an observational database study, and targeted follow-up of cases of special interest will be instituted for this important topic.8

Figure 1. Incidence Rate and 95% CI by Analysis Dataset for Malignancies Excluding Non-Melanoma Skin Cancer Through February 13, 20188

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

Figure 2. Incidence Rate and 95% CI by Reporting Time Period for Malignancies Excluding Non-Melanoma Skin Cancer Through February 13, 20188

Abbreviations: BARI = baricitinib; n = number of patients with events; NAR = number of patients at risk; PYE = patient-years of exposure.

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.1

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenic potential.1

Malignancy

The incidence of malignancy, excluding non-melanoma skin cancer, in the BARI clinical RA program appears to be similar to the incidence reported in other RA therapeutic programs.2-7

Identification and Analysis of Malignancies

According to standard conventions, the reporting for malignancy was broken into subcategories for NMSC and malignancies excluding NMSC, each with their own set of preferred terms from the standardized MedDRA query SMQ 20000194.8

Analyses were conducted using integrated safety datasets including the

  • 6 study dataset, which evaluated patients administered BARI 4 mg, BARI 2 mg, or placebo through 24 weeks

  • All BARI RA dataset, which evaluated 3492 patients with RA from 8 randomized studies and 1 long-term extension study with data through 01 April 2017, and

  • 4 study extended dataset, which evaluated patients administered BARI 4 mg or BARI 2 mg with long-term extension data through 01 April 2017.7,9

These safety data were censored at rescue or dose change, defined as an “as-treated analysis.” The 4 study extended dataset was also evaluated without censoring for rescue or dose change, defined as an “as-randomized” analysis, to account for the long latency period of most cancers. The data in the All BARI RA dataset were not censored.9

Malignancy Excluding Non-Melanoma Skin Cancers

24-Week Placebo-Controlled Period - 6 Study Dataset

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

  • 0.5 in the BARI 4-mg group (n=997)

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

  • 0.5 in the placebo group (n=1070).9

All BARI RA Dataset

In the All BARI RA dataset, with data through 01 April 2017, there were 63 reported cases of malignancy excluding NMSC representing an IR of 0.8 per 100 PYs.9

The IRs and 95% CIs for malignancies excluding NMSC in each integrated dataset through 01 April 2017 as well as individual comparator studies, RA-BEAM and RA-BEGIN, are provided in Figure 3

The IRs remained stable in the All BARI RA dataset with prolonged treatment.9 See details in Figure 4

BARI 4 mg vs BARI 2 mg - 4 Study Extended Dataset

The IRs per 100 PYs for malignancies excluding NMSC across additional analyses in the 4 study extended dataset, with data through 01 April 2017, were

  • 1.2 in the BARI 4-mg group compared with 0.5 in the BARI 2-mg group for the “as-treated” analysis, and

  • 0.8 in both the BARI 4-mg and BARI 2-mg groups for the “as-randomized” analysis.9

Lymphoma

There were no cases of lymphoma reported for patients administered BARI in the randomized, controlled periods of the RA clinical program.7

In the All BARI RA dataset, with data through 01 April 2017, 6 cases of lymphoma were reported during the long-term extension study (IR 0.08 per 100 PY) including

  • 1 patient who initiated treatment with BARI 4 mg

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

  • 4 patients who initially received placebo were then switched or rescued to BARI 4 mg.7,9

Background methotrexate was administered in 5 out the 6 patients, and the other patient received concomitant tacrolimus.7

Lymphoproliferative Disorders

Two cases of lymphoproliferative disorder were reported including

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

  • 1 patient diagnosed 112 days after rescue to BARI 4 mg from initial treatment with adalimumab.7

Non-Melanoma Skin Cancers

24-Week Placebo-Controlled Period - 6 Study Dataset

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

  • 0.7 in the BARI 4 mg group (n=997)

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

  • 0.2 in the placebo group (n=1070).9

All BARI RA Dataset

In the All BARI RA dataset, with data through 01 April 2017, there were 30 reported cases of NMSC representing an IR of 0.4 per 100 PYs.9

BARI 4 mg vs BARI 2 mg - 4 Study Extended Dataset

The IRs per 100 PY for NMSC, with "as-treated" data through 01 April 2017, were 1.1 for BARI 4 mg compared with 0.3 for BARI 2 mg.9

Pharmacovigilance

Appropriate pharmacovigilance, including analysis of ongoing and planned clinical studies, observational postmarketing safety studies, an observational database study, and targeted follow-up of cases of special interest will be instituted for this important topic.8

Figure 3. Incidence Rate and 95% CI by Analysis Dataset for Malignancies Excluding Non-Melanoma Skin Cancer Through 01 April 20178,9

Abbreviations: ADA = adalimumab; BARI = baricitinib; CI = confidence interval; DMARD = disease-modifying antirheumatic drug; IR = inadequate responder; Mono = monotherapy; MTX = methotrexate; PBO = placebo; PYE = patient-years of exposure; wks = weeks.

Figure 4. Incidence Rate and 95% CI by Reporting Time Period for Malignancies Excluding Non-Melanoma Skin Cancer Through 01 April 20179

Abbreviations: BARI = baricitinib; CI = confidence interval; n = number of patients with events; NAR = number of patients at risk; PYE = patient-years of exposure.

References

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

2. Gottlieb AB, Gordon K, Giannini EH, et al. Clinical trial safety and mortality analyses in patients receiving etanercept across approved indications. J Drugs Dermatol. 2011;10(3):289-300. https://www.ncbi.nlm.nih.gov/pubmed/21369647

3. Burmester GR, Panaccione R, Gordon KB, et al. Adalimumab: long-term safety in 23,458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis. 2013;72(4):517-524. http://dx.doi.org/10.1136/annrheumdis-2011-201244

4. Curtis JR, Lee EB, Kaplan IV, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid arthritis clinical development programme. Ann Rheum Dis. 2016;75(5):831-841. http://dx.doi.org/10.1136/annrheumdis-2014-205847

5. Curtis JR, Lee EB, Martin G, et al. Analysis of non-melanoma skin cancer across the tofacitinib rheumatoid arthritis clinical programme. Clin Exp Rheumatol. 2017;35(4):614-622. http://www.clinexprheumatol.org/abstract.asp?a=11224

6. Schiff MH, Kremer JM, Jahreis A, et al. Integrated safety in tocilizumab clinical trials. Arthritis Res Ther. 2011;13(5):R141. http://dx.doi.org/10.1186/ar3455

7. 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

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

9. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 6 years: an updated integrated safety analysis. Poster presented at: Annual Meeting of the American College of Rheumatology (ACR); October 20-24, 2018; Chicago, IL.

10. Genovese MC, Smolen JS, Takeuchi T, et al. Safety profile of baricitinib for the treatment of rheumatoid arthritis up to 7 years: an updated integrated safety analysis. Ann Rheum Dis. 2019;78(2):308-309. http://dx.doi.org/10.1136/annrheumdis-2019-eular.691

Glossary

BARI = baricitinib

CI = Confidence Interval

IR = incidence rate

MedDRA = Medical Dictionary for Regulatory Activities

NMSC = nonmelanoma skin cancer

PY(s) = patient year(s)

RA = rheumatoid arthritis

SMQ = standardized MedDRA query

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 2018 M10 05

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