Olumiant ® (baricitinib) tabletter

För fullständig produktresumé för Olumiant se FASS.

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Olumiant® ▼ (baricitinib): Övergripande och allvarliga infektioner

En ökning av de totala infektionerna, men inte allvarliga infektioner, observerades mellan baricitinib och placebo i det kliniska programmet för reumatoid artrit.

Information from the label

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. 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

In controlled studies, for up to 16 weeks, the incidence rate of all infections (rate of patients with ≥ 1 event per 100 patient-years of exposure) was 101 with baricitinib compared to 83 in the placebo group. Most infections were mild to moderate in severity. In studies which included both doses, infections were reported in 31.9 %, 28.8 % and 24.1 % of patients up to 16 weeks in the 4 mg, 2 mg and placebo groups, respectively. Reporting rates for baricitinib compared to placebo for the infection-related ADRs were: Upper respiratory tract infections (14.7 % vs. 11.7 %), urinary tract infections (3.4 % vs. 2.7 %), gastroenteritis (1.6 % vs. 0.8 %), herpes simplex (1.8 % vs. 0.7 %), and herpes zoster (1.4 % vs. 0.4 %). In treatment-naïve patients, for up to 52 weeks, the frequency of upper respiratory tract infections was greater for the combination treatment of methotrexate and baricitinib (26.0 %) compared to methotrexate alone (22.9 %) or baricitinib alone (22.0 %). The rate of serious infections with baricitinib (1.1 %) was similar to placebo (1.2 %). For baricitinib, the most common serious infections were herpes zoster, and cellulitis. The rate of serious infections remained stable during long term exposure. The overall incidence rate of serious infections in the clinical trial programme was 3.2 per 100 patient-years.1

Mean absolute lymphocyte count increased by 1 week after starting treatment with baricitinib, returned to baseline by week 24, and then remained stable through at least 104 weeks. For most patients, changes in lymphocyte count occurred within the normal reference range.1

In controlled studies, for up to 16 weeks, neutropaenia (<1 x 109 cells/L) was uncommonly reported (≥ 1/1,000).1

In controlled studies, for up to 16 weeks, decreases in neutrophil counts below 1 x 109 cells/L occurred in 0.3 % of patients treated with baricitinib compared to 0 % of patients treated with placebo. There was no clear relationship between decreases in neutrophil counts and the occurrence of serious infections. However, in clinical studies, treatment was interrupted in response to ANC < 1 x 109 cells/L. The pattern and incidence of decreases in neutrophil counts remained stable at a lower value than baseline over time including in the long-term extension study.1

Treatment should not be initiated in patients with an absolute lymphocyte count (ALC) less than 0.5 x 109 cells/L, an absolute neutrophil count (ANC) less than 1 x 109 cells/L, or who have a haemoglobin value less than 8 g/dL. Treatment may be initiated once values have improved above these limits.1

Additional Infection Information

Information regarding cases of herpes zoster, tuberculosis, and opportunistic infections, reported in the clinical development program are not discussed in this response.

All Infections

Exposure-adjusted incidence rates were calculated as the number of patients with an event per 100 patient-years of exposure time, with exposure not censored at time of event.2

7-Study Placebo-Controlled Dataset

Description of 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.2,3

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).2,3

Incidence of Infections

Through 24 weeks of assigned treatment or until rescue, the number of patients with any type of TE infection was

  • 423 (EAIR=89.7) in the BARI 4-mg group

  • 156 (EAIR=84.0) in the BARI 2-mg group, and

  • 340 (EAIR=75.4) in the placebo group.4

Commonly reported infections with BARI treatment include

  • upper respiratory tract infections

  • herpes zoster infection, and

  • herpes simplex infections.4

Serious Infections

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.2

Clinical Factors Associated With Serious Infection

A large group of clinical factors with the potential to affect the risk of serious infection was evaluated using Cox models and data from the All BARI RA dataset through 01 January 2016. The 5 independent risk factors identified for serious infection were

  • prior biologic use

  • advanced age

  • Asian region of study enrollment, excluding Japan

  • non-normal body mass index, and

  • concomitant corticosteroid use.5

As discussed below, increasing grades of lymphopenia were associated with an increase in frequency of serious infection in BARI-treated patients.4

Incidence of Serious Infections in the Baricitinib Clinical Program

7-Study Placebo-Controlled Dataset

Through 24 weeks of assigned treatment or until rescue, the number of patients with a TE serious infection was

  • 19 (IR=4.0) in the BARI 4-mg group

  • 8 (IR=4.2) in the BARI 2-mg group, and

  • 19 (IR=4.1) in the placebo group.3

4-Study Extended Dataset

Description of Dataset

The extended dataset included patients with RA randomized to BARI 4 mg (N=479, PYE=698.6) or BARI 2 mg (N=479, PYE=675.6) 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 13 February 2018 unless otherwise specified. Data were censored at rescue or dose change.32

Incidence of Serious Infection

The rate of TE serious infection was numerically lower in the BARI 2-mg group (n=21, IR=3.1) than the BARI 4-mg group (n=32, IR=4.6) through 13 February 2018.3

All BARI RA Dataset

Description of 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

  • data through 13 February 2018, and

  • 10,127 PYE.2,3

Incidence of Serious Infection

Of the 3770 patients who received BARI in the RA clinical trials through 13 February 2018, there were 283 TE serious infections with an IR per 100 PYE, of 2.8. The most frequent serious infections reported were

  • pneumonia (n=56, EAIR 0.54)

  • herpes zoster (n=35, EAIR 0.34)

  • urinary tract infection (n=23, EAIR 0.22)

  • cellulitis (n=16, EAIR 0.16)

  • sepsis (n=18 including 14 cases of sepsis and 4 cases of urosepsis), and

  • gastroenteritis (n=13, EAIR 0.13).3,4

Rates of serious infection remained similar over time with extended treatment through 13 February 2018.3

Lymphopenia and Neutropenia and Potential Infection Risk

Lymphocyte and Infection Risk

Increasing grades of lymphopenia were associated with an increase in frequency of any TE infection and serious infection in BARI-treated patients.4 

Neutropenia and Infection Risk

Increasing grades of neutropenia was not consistently associated with an increase in frequency of any TE infection or serious infection in BARI-treated patients.4 

References

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

2. 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. Presented as an oral presentation at: European League Against Rheumatism (EULAR) Annual Meeting; June 12-15, 2019; Madrid, Spain.

3. 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

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

5. Winthrop KL, Genovese MC, Harigai M, et al. Serious infection and associated risk factors in patients with moderate to severe rheumatoid arthritis treated with baricitinib [abstract OP0248]. Ann Rheum Dis. 2017;76(suppl 2):158. http://ard.bmj.com/content/76/Suppl_2/158.2

Glossary

BARI = baricitinib

DMARD = disease-modifying antirheumatic drug

EAIR = exposure-adjusted incidence rate

IR = incidence rate

MTX = methotrexate

PYE = patient-years of exposure

RA = rheumatoid arthritis

TE = treatment-emergent

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 2019 M03 12

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