Olumiant ® (baricitinib) tabletter

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Olumiant® ▼ (baricitinib): Förändringar i hemoglobin

Jämfört med placebo var ingen av baricitinibdoserna associerade med en ökad förekomst av erythropenia som biverkning.

Information from the label

Hemoglobin < 8 g/dL were reported in less than 1 % of patients in clinical trials. Treatment should not be initiated, or should be temporarily interrupted, in patients with hemoglobin < 8 g/dL observed during routine patient management. Treatment may be initiated once values have improved above these limits.1

Haemoglobin should be assessed before treatment initiation and thereafter according to routine patient management.1

Role of JAK2 in Erythropoietin Function

Erythropoietin signals through JAK2 and inhibition of the JAK/stat pathway affects erythropoiesis and hemoglobin.2,3

Hemoglobin Changes Over Time

The 5-study pooled dataset included patients with RA randomized to BARI 4 mg or placebo from 1 phase 2 study and 4 phase 3 studies (RA-BEAM, RA-BUILD, RA-BEACON and RA-BALANCE). Data includes a long-term extension study (RA-BEYOND) with data through 13 February 2018.4

BARI 2 mg data is pooled from 3 of these studies in which both BARI 2 mg and BARI 4 mg were options during randomization (1 phase 2 studies as well as RA-BUILD and RA-BEACON).4

In 5 pooled studies including extension data through 13 February 2018, initial mean decreases in hemoglobin observed with BARI treatment

  • increased towards baseline levels starting at week 16,

  • corresponded to the timing and volume of blood draws, and 

  • mean levels remained above baseline and relatively stable at a higher level thereafter through 216 weeks (Figure 1).4

Figure 1. Mean Changes in Hemoglobin Over Time From 5 Pooled Studies4

Abbreviations: BARI = baricitinib; PBO = placebo.

Notes: BARI 2 mg, placebo censored at rescue or dose change, and BARI 4 mg censored at any dose change (including step=down) or rescue in RA-BEYOND.

Abnormal Low Hemoglobin Values

Categorical changes in hemoglobin values were assessed by determining the proportion of patients who had a

  • TE value below the LLN, and

  • TE increase in CTCAE grade for low hemoglobin.4

CTCAE Grades for Low Hemoglobin Defined

  • Grade 0: (normal) ≥7.27 mmol/L (12.0 g/dL) for women (≥8.18 mmol/L [13.5 g/dL] for men).

  • Grade 1: <7.27 mmol/L (12 g/dL) for women (<8.18 mmol/L [13.5 g/dL] for men) and ≥6.2 mmol/L (10.0 g/dL).

  • Grade 2: <6.2 mmol/L (10.0 g/dL) and ≥4.9 mmol/L (8.0 g/dL).

  • Grade 3: <4.9 mmol/L (8.0 g/dL) and ≥4.0 mmol/L (6.5 g/dL).

  • Grade 4: <4.0 mmol/L (6.5 g/dL).4

Treatment-Emergent Hemoglobin Low Defined

Treatment emergent abnormal low was defined as number of cases with post-baseline scores <LLN. 

  • Number at risk for the TE abnormal low was defined as the number of patients with a value ≥ to the LLN at all baseline visits.

  • The LLN values are different by patient depending on age and sex.4

7-Study Placebo-Controlled Dataset

Abnormal Low Hemoglobin Values

Through 24 weeks of assigned treatment or until rescue the proportion of patients with a TE abnormal low hemoglobin value was

  • 30.7% in the 4-mg group, 

  • 26.5% in the 2-mg group, and

  • 26.7% in the placebo group.4,5

Few patients had a worsening in hemoglobin CTCAE grade from <3 to ≥3

  • 0.2% in the BARI 4-mg group,

  • 0.4% in the BARI 2-mg group, and

  • 0.2% in the placebo group.4

4-Study Extended Dataset

Abnormal Low Hemoglobin Values

Through 13 February 2018 the proportion of patients with a TE abnormal low hemoglobin value was not statistically significantly different between the BARI 4-mg and 2-mg groups (35.6% vs 33.2%).4

Few patients had a worsening in hemoglobin CTCAE grade from <3 to ≥3 in the BARI 4-mg and 2-mg groups (0.2% vs 0.6%).4

All BARI RA Dataset

Abnormal Low Hemoglobin Values

Through 13 February 2018 the proportion of patients with a TE abnormal low hemoglobin value was 1073 (40.3%).4

A shift to CTCAE grade 3 indicates that hemoglobin levels have dropped below 4.9 mmol/L (8.0 g/dL). There were 31 (0.8%) BARI-treated patients in the All BARI RA dataset (N=3770) with a reported TE decrease in hemoglobin levels to CTCAE grade ≥3.4

Among the 31 BARI-treated patients with a shift to hemoglobin grade ≥3,

  • there was no apparent pattern to the timing of the hemoglobin decreases

  • all of the patients classified as having consecutive abnormal observations at grade ≥3 (n=7) had abnormal low hemoglobin at baseline, and

  • the majority of patients with a shift to grade ≥3 had additional risk factors upon entry into the study, which included, or were indicated by

    • anemia or iron deficiency anemia

    • chronic gastritis, gastroesophageal reflux disease, or gastric antral vascular ectasia, and

    • prior pantoprazole administration.4

There were 26 patients who had a temporary interruption of BARI treatment due to anemia; treatment was restarted in 18 of these patients.4

Reported Adverse Events of Anemia

Evaluation of TEAEs of anemia included MedDRA preferred terms, anemia and iron deficiency anemia, from the Blood and Lymphatic System Disorders System Organ Class.4 Percentages by treatment group and EAIR are provided below.  

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.6

7-Study Placebo-Controlled Dataset

Through 24 weeks of assigned treatment or until rescue, the rates of anemia were

  • 3.2% (EAIR 7.8) in the BARI 4-mg group, 

  • 1.9% (EAIR 4.8) in the BARI 2-mg group, and

  • 3.1% (EAIR 8.4) in the placebo group.4,5

Through 24 weeks of assigned treatment or until rescue, the rates of iron deficiency anemia were

  • 0.2% (EAIR 0.4) in the BARI 4-mg, 

  • 0.4% (EAIR 1.1) in the BARI 2-mg, and

  • 0.2% (EAIR 0.4) placebo group.4,5

4-Study Extended Dataset

In the 4-study extended dataset with data through 13 February 2018,

  • rates of anemia were

    • 3.3% (EAIR 2.3) in the BARI 4-mg group, and

    • 2.5% (EAIR 1.8) in the 2-mg group,

  • rates of iron deficiency anemia were

    • 0.6% (EAIR 0.4) in the BARI 4-mg group, and

    • 0.6% (EAIR 0.4) in the 2-mg group.4

All BARI RA Dataset

In the All BARI RA analysis through 13 February 2018 

  • rates of anemia were 5.4% (EAIR 2.0),

  • rates of iron deficiency anemia were 0.7% (EAIR 0.3).4

Temporary Interruption and Permanent Discontinuation Due to Low Hemoglobin

7-Study Placebo-Controlled Dataset

Temporary interruption of study drug due to the TEAEs of anemia occurred with similar frequency

  • 1 patients in the BARI 4-mg group, 

  • 0 patients in the BARI 2-mg group, and

  • 2 patient in the placebo group.4,5

Permanent discontinuation of study drug due to the TEAEs of anemia occurred with similar frequency 

  • 2 patients in the BARI 4-mg group,

  • 2 patient in the BARI 2-mg group, and

  • 0 patients in the placebo group.4,5

4-Study Extended Dataset

In the 4-study extended dataset with data through 13 February 2018, anemia or iron deficiency anemia led to

  • temporary interruption of study treatment in

    • 2 patients in the BARI 4-mg group, and

    • 0 patients in the BARI 2-mg group,  

  • permanently discontinuation of study treatment in

    • 2 patients permanently discontinued treatment in the BARI 4-mg group, and

    • 3 patients permanently discontinued treatment in the BARI 2-mg group.4

All BARI RA Dataset

In the All BARI RA analysis through 13 February 2018, anemia or iron deficiency anemia led to

  • temporary interruption of study treatment in 10 patients, and 

  • permanently discontinuation of study treatment in 17 patients.4

References

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

2. Fridman JS, Scherle PA, Collins R, et al. Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol. 2010;184(9):5298-5307. http://dx.doi.org/10.4049/jimmunol.0902819

3. Levine RL, Pardanani A, Tefferi A, Gilliland DG. Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders. Nature Rev Cancer. 2007;7(9):673-683. http://dx.doi.org/10.1038/nrc2210

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

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. 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.

Glossary

BARI = baricitinib

CTCAE = Common Terminology Criteria for Adverse Events

EAIR = exposure-adjusted incidence rate

JAK = Janus kinase

LLN = lower limit of normal

MedDRA = Medical Dictionary for Regulatory Activities

RA = rheumatoid arthritis

TE = treatment-emergent

TEAE = treatment-emergent adverse event

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 M08 23

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