Olumiant® ▼ (baricitinib): Herpes Zoster vid reumatoid artrit

Information on Adverse Reaction from the Label

Herpes zoster was commonly reported with baricitinib in placebo-controlled studies for up to 16 weeks (≥ 1/100 to < 1/10). Reporting rates for baricitinib compared to placebo for herpes zoster were 1,4 % vs. 0,4 %.¹

The Use of Baricitinib and Herpes Zoster

Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster, herpes simplex), were reported in clinical studies. Herpes zoster was reported more commonly in patients ≥ 65 years of age who had previously been treated with both biologic and conventional DMARDs.¹

If a patient develops herpes zoster, baricitinib treatment should be temporarily interrupted until the episode resolves.¹

However, in the RA long-term extension study, if a patient was diagnosed with HZ, the investigator was instructed to

• interrupt the study treatment

• initiate standard of care

• monitor for multidermatomal involvement or other evidence of dissemination, and

• follow-up until clinical recovery of skin lesions or vesicles.²

Study treatment could be resumed when skin lesions were crusted and resolving.³

Incidence of Herpes Zoster in Baricitinib Rheumatoid Arthritis Clinical Trials

The HZ cluster of preferred terms was used to identify cases of HZ in the BARI safety database. 

Incidence rates were calculated as the number of patients with an event per 100 patient-years of exposure time, with exposure censored at time of event.⁴

7-Study Placebo-Controlled Dataset

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.⁴

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).⁴

Through 24 weeks of assigned treatment or until rescue, the HZ IR for BARI 4-mg group (4.4) was statistically significantly higher than the placebo group (1.1; p<.05) and numerically higher than BARI 2-mg group (3.1).⁴

4-Study Extended Dataset

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

In the 4-study extended dataset, the EAIR of HZ infections was numerically but not statistically significantly higher in the BARI 4-mg group (EAIR=3.1) than the BARI 2-mg group (EAIR=2.7).²

All BARI RA Dataset

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.^5,6

Of the 3770 patients who received BARI in clinical trials for the treatment of RA with a total of 13,148 PYE,  

• 384 had a treatment-emergent case of HZ, and

• the overall IR was 3.0/100 PYs of observation.⁵

Of the 384 HZ cases reported,

• 95% of cases were mild to moderate in severity

• 8% of cases were multidermatomal, and

• 0 had visceral involvement.²

Based on multivariate analyses, a higher risk of HZ was associated with

• older age (≥50 vs <50, HR=1.94 [95% CI 1.49, 2.52], and

• the geographical region of Asia (Asia vs US + Canada, HR=1.57 [95% CI 1.14, 2.17]).^4,7

Herpes Zoster Vaccinations

No data are available on the response to vaccination with live vaccines in patients receiving baricitinib. Use with live, attenuated vaccines during, or immediately prior to, baricitinib therapy is not recommended.¹

Prior to initiating baricitinib, it is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines.¹

For further information please refer to "2019 update of EULAR recommendations for Vaccination in Adult Patients with Autoimmune Inflammatory Rheumatics" available on the EULAR website.⁸

No information is available regarding the use of BARI with a non-live HZ vaccine, such as Shingrix, because

• non-live HZ vaccine was not available at the time of the RA phase 3 studies, and

• no additional studies with the non-live vaccine have been conducted.

As recommendations regarding vaccination may vary, please follow local guidance and local labeling regarding the administration of vaccines, including the live attenuated and non-live HZ vaccines, to patients with autoimmune diseases.

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. Winthrop KL, Harigai M, Genovese MC, et al. Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Ann Rheum Dis. Published online August 11, 2020. http://dx.doi.org/10.1136/annrheumdis-2019-216852

4. 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

5. 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

6. 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.

7. Chen YH, Chen YM, Smolen J, et al. Incidence rate and characterisation of herpes zoster events in patients with moderate to severe rheumatoid arthritis: an update from baricitinib clinical trials. Poster presented at: European League Against Rheumatism (EULAR) Annual Meeting; June 12-15, 2019; Madrid, Spain.

8. Furer V, Rondaan C, Heijstek MW, et al. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Ann Rheum Dis. 2020;79(1):39-52. http://dx.doi.org/10.1136/annrheumdis-2019-215882

Glossary

BARI = baricitinib

DMARD = disease-modifying antirheumatic drug

EAIR = exposure-adjusted incidence rate

HZ = herpes zoster

IR = incidence rate

MTX = methotrexate

PYE = patient-years of exposure

RA = rheumatoid arthritis

Shingrix = Shingrix^TM (Zoster Vaccine Recombinant, Adjuvanted) 

▼ 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.