Olumiant ® ▼ (baricitinib)

This information is intended for UK registered healthcare professionals only as a scientific exchange in response to your search for information. Please refer to the link for full prescribing information: Olumiant Summary of Product Characteristics (SmPC)

Olumiant® ▼ (baricitinib): Malignancy and Lymphoproliferative Disorders in Atopic Dermatitis

In the atopic dermatitis clinical trials, there were 5 reports of malignancies 6 reports of non-melanoma skin cancers in all baricitinib treated patients; there were no differences between placebo and BARI groups in the placebo-controlled period.

Warnings and Precautions Related to Malignancy

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

Baricitinib Genotoxicity and Carcinogenicity

Non-clinical data reveal no special hazard for humans based on conventional studies of

  • safety pharmacology,

  • genotoxicity and

  • carcinogenic potential.1

Baricitinib was not genotoxic in the

  • bacterial mutagenicity assay (Ames assay)

  • in vitro chromosomal aberration assay using cultured human lymphocytes, or

  • in vivo micronucleus assay in the rat.2,3

Baricitinib did not produce neoplastic changes in 2-year rat and 6-month transgenic mouse carcinogenicity studies.2,3

Risk of Malignancies in Patients With Atopic Dermatitis

Published literature regarding risk of various malignancies in patients with AD is inconclusive. Based on the literature, patients with AD may have

  • no increased risks for malignancies overall4,5

  • increased risk for skin cancers, including melanoma and nonmelanoma skin cancers4,5, and

  • a slight increased risk of lymphoma, with severity of AD as a significant risk factor.5,6

Atopic Dermatitis Clinical Trial Criteria Related to Malignancies

Patients were excluded from enrollment in the AD clinical trials if they had

  • a history of lymphoproliferative disease

  • signs or symptoms suggestive of possible lymphoproliferative disease, including lymphadenopathy or splenomegaly

  • active primary or recurrent malignant disease, or

  • remission from clinically significant malignancy for <5 years.2

Patients were allowed to participate in the AD clinical trials if they had

  • cervical carcinoma in situ that has been appropriately treated with no evidence of recurrence or metastatic disease for ≥3 years, or

  • basal cell or squamous epithelial skin cancers that have been appropriately treated with no evidence of recurrence for ≥3 years.2

Patients were discontinued from study drug if a treatment-emergent malignancy occurred during the clinical trials. However, patients with successfully treated basal or squamous cell skin carcinoma could continue on study drug.2

Incidence of Malignancies in Baricitinib Atopic Dermatitis Clinical Trials

The integrated safety datasets used to evaluate treatment-emergent malignancies are described in Table 2.

Malignancy, NMSC, and lymphoproliferative events across all safety datasets are presented in Table 1.

Malignancy Excluding Nonmelanoma Skin Cancer

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 20000194.2

Placebo-Controlled Period

Through 16 weeks, there were no reports of malignancy excluding NMSC in the BARI 2 mg or BARI 4 mg groups and 2 reports in the placebo group (breast cancer n=1; papillary thyroid cancer n=1).2

All Baricitinib-Treated Patients With Extended Data

Of the 2531 patients treated with all BARI doses in the AD clinical trials, 5 (IR=0.22) had a reported malignancy excluding NMSC. The 5 cases included 

  • 1 event of anaplastic large cell lymphoma T- and null cell type while on BARI 4 mg (considered related to study drug by investigator)

  • 1 event of B-cell lymphoma while on BARI 2 mg (considered unrelated to study drug by investigator)

  • 1 event of diffuse large B-cell lymphoma while on BARI 2 mg (considered related to study drug by investigator)

  • 1 event of prostate cancer while on BARI 2 mg (considered unrelated to study drug by investigator), and 

  • 1 event of rectal cancer while on BARI 2 mg (considered unrelated to study drug by investigator).2

Time on BARI treatment to event ranged from 52 days to 422 days.2

Nonmelanoma Skin Cancer

All the cases identified by the malignant tumors SMQ were assessed through medical review to determine confirmed NMSC cases. Cases of NMSC were defined by 12 terms that included

  • squamous cell carcinoma of skin 

  • Bowen’s disease

  • basal cell carcinoma

  • basosquamous carcinoma

  • basosquamous carcinoma of skin

  • squamous cell carcinoma

  • skin squamous cell carcinoma metastatic

  • skin cancer

  • carcinoma in situ of skin

  • keratoacanthoma

  • vulvar squamous cell hyperplasia, and

  • skin squamous cell carcinoma recurrent.2

Placebo-Controlled Period

Through 16 weeks, there were no reports of NMSC in the BARI 2 mg or BARI 4 mg groups and 1 report in the placebo group (Bowen's disease n=1).2

All Baricitinib-Treated Patients With Extended Data

Of the 2531 patients treated with all BARI doses in the AD clinical trials, 6 (IR=0.26) had a reported NMSC. The 6 cases included 

  • 3 events of basal cell carcinoma (BARI 2 mg n=3)

  • 2 events of Bowen's disease (BARI 1 mg n=1, BARI 4 mg n=1), and 

  • 1 event of keratoacanthoma (BARI 1 mg n=1).2

Time on BARI treatment to event ranged from 5 days to 206 days.2

Table 1. Malignancies and Nonmelanoma Skin Cancers in Atopic Dermatitis Clinical Trials2

 

 

 

 

 

 

 

 

 

 

 

BARI 2 mg Placebo-Controlleda
n (adj %)
b

BARI 4 mg Placebo-Controlleda
n (adj %)
b

BARI 2 mg vs 4 mga
n (adj %)
b

BARI 2 mg vs 4 mg ext
n (adj %)
b [adj IR]

All BARI AD
n (%) [IR]


Placebo
n=889

BARI 2 mg
n=721

Placebo
n=743

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

BARI 2 mg
n=576

BARI 4 mg
n=489

All Doses
N=2531

Malignancy excluding NMSC

2 (0.2)

0

2 (0.2)

0

0

0

0

0

5 (0.2) [0.22]

NMSC

1 (0.2)

0

1 (0.2)

0

0

0

0

0

6 (0.2) [0.26]

Lymphoproliferative disorder

0

0

0

0

0

0

0

0

0

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; ext = extended; IR = incidence rate; NMSC = non-melanoma skin cancer.

a Data through 16-week placebo-controlled period.

b For the integrated controlled analysis sets where the randomized ratio of patients receiving BARI to placebo or BARI to active control is not the same across all the integrated studies (eg, 2:1:1:1 vs 1:1:1:1), the study-size adjusted percentages were calculated for the adverse events to provide appropriate direct comparisons between treatment groups. 

Integrated Safety Datasets Table

Table 2. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2

Analysis Set

Description

BARI 2 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, BREEZE- AD5, and BREEZE-AD7

Compares BARI 2 mg vs placebo

Includes patients with AD from 1 phase 2 and 5 phase 3 studies who were randomized to

  • BARI 2 mg (n=721, PYE=210.6), or

  • placebo (n=889, PYE=252.7).

Treatment period was 0 to 16 weeks.

BARI 4 mg Placebo-Controlled

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE- AD4, and BREEZE-AD7

Compares BARI 4 mg vs placebo

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 4 mg (n=489, PYE=147.1), or

  • placebo (n=743, PYE=211.8).

Treatment period was 0 to 16 weeks.

BARI 2 mg vs 4 mg

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, and BREEZE-AD7

Compares BARI 2 mg vs BARI 4 mg through 16 weeks

Includes patients with AD from 1 phase 2 and 4 phase 3 studies who were randomized to

  • BARI 2 mg (n=576, PYE=169.1), or

  • BARI 4 mg (n=489, PYE=147.1).

Treated for 0 to 16 weeks during the placebo-controlled period.

BARI 2 mg vs 4 mg Extended

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD7, and extension study BREEZE-AD3

Compares BARI 2 mg vs BARI 4 mg including extended evaluations

Includes patients with AD from 1 phase 2 and 4 phase 3 studies and any further exposure for those patients in the phase 3 extension study, BREEZE-AD3, who were randomized to

  • BARI 2 mg (n=576, PYE=425.5), or

  • BARI 4 mg (n=489, PYE=459.3).

Data censored at dose or treatment change (rescue, dose switch, or re-randomization to a different BARI dose or placebo) for BREEZE-AD4 and BREEZE-AD3.

All BARI AD

Studies: JAHG, BREEZE-AD1, BREEZE-AD2, BREEZE-AD4, BREEZE-AD5, BREEZE-AD7, and extension studies BREEZE-AD3, BREEZE-AD6

No between-group comparisons

Includes 2531 (total PYE=2247.4) patients with AD from 1 phase 2, 5 phase 3, and 2 phase 3 extension studies who received BARI at a variety of doses, including

  • BARI 1 mg (n = 538, PYE = 245,9)

  • BARI 2 mg (n=1580, PYE=1129.5), and

  • BARI 4 mg (n=914, PYE=872.8).

Includes all patients who were exposed to any BARI dose at any time during the studies, either from randomization or from switch or rescue from placebo.

 No censoring of data at dose change.

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; PYE = patient-years of exposure.

Note: BARI 1 mg was studied in pivotal trials, however it is not approved. Please refer to Olumiant Summary of Product Characteristics for recommended dose.

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. Carfagna M, Cannady E, Ryan T, et al. Carcinogenicity assessment of baricitinib in Tg.rasH2 mice and Sprague-Dawley (Crl:CD) rats. Regul Toxicol Pharmacol. 2018;92:458-471. https://www.ncbi.nlm.nih.gov/pubmed/29203403

4. Andersen YMF, Egeberg A, Skov L, et al. Comorbidities of atopic dermatitis: beyond rhinitis and asthma. Curr Dermatol Rep. 2017;6(1):35-41. http://dx.doi.org/10.1007/s13671-017-0168-7

5. Paller A, Jaworski JC, Simpson EL, et al. Major comorbidities of atopic dermatitis: beyond allergic disorders. Am J Clin Dermatol. 2018;19 (6):821-838. http://dx.doi.org/10.1007/s40257-018-0383-4

6. Legendre L, Barnetche T, Mazereeuw-Hautier J, et al. Risk of lymphoma in patients with atopic dermatitis and the role of topical treatment: a systemic review and meta-analysis. J Am Acad Dermatol. 2015;72(6):992-1002. http://dx.doi.org/10.1016/j.jaad.2015.02.1116

Glossary

AD = atopic dermatitis

BARI = baricitinib

IR = incidence rate

MedDRA = Medical Dictionary for Regulatory Activities

NMSC = nonmelanoma skin cancer

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.

Date of Last Review: August 17, 2020


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