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): Changes in Creatine Phosphokinase in the Rheumatoid Arthritis Clinical Development Program

In the RA clinical trials, mean increases in CPK were mostly observed with BARI 4 mg from 0 to 8 week and remain stable thereafter. There was no evidence that baricitinib (BARI) treatment increased the risk of serious muscle-related adverse events.

Changes in Creatine Phosphokinase Levels Over Time in Rheumatoid Arthritis Clinical Trials

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 2018.1

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 study as well as RA-BUILD and RA-BEACON).1

In 5 study pooled dataset phase 3 studies 

  • mean increases in CPK were mostly observed with BARI 4 mg from 0 to 8 weeks, and

  • mean CPK levels remained relatively stable at a higher level thereafter through 216 weeks (see Figure 1).1

Figure 1. Mean Changes in CPK Over Time From 5-Study Pooled Dataset  in Rheumatoid Arthritis Studies1

Abbreviations: BARI = baricitinib; CPK = creatine phosphokinase; 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. Data through 13 February 2018.

Treatment-Emergent Abnormal Creatine Phosphokinase Values in Rheumatoid Arthritis Clinical Trials

7-Study Placebo-Controlled Dataset

The proportions of patients with an increase in grade from <3 to ≥3 or from <4 to ≥4 were not statistically significantly different between the BARI 4-mg group and the placebo group.1 For additional details see Table 1.

4-Study Extended Dataset

In the 4-study extended dataset through 13 February 2018, the proportions of patients were not statistically different between the BARI 4-mg (N=479, PYE=698.6, median exposure=342 days, maximum exposure=2520 days) and BARI 2-mg group (N=479, PYE=675.6, median exposure=257 days, maximum exposure=1805 days) for categorical changes in CPK grade from

  • grade <3 to ≥3, and

  • grade <4 to ≥4.1,2

Data on the proportions of patients who reported categorical changes in CPK grade is provided in Table 1.

All BARI RA Dataset

For information on the proportions of patients with categorical changes in CPK grades in the All BARI RA analysis, see Table 1.

Table 1. Overview of CTCAE Grade Shifts in Creatine Phosphokinase in Rheumatoid Arthritis Trials1,2

 

Shift from:

Grade <1 to ≥1

n/NAR (%)

Shift from:

Grade <2 to ≥2

n/NAR (%)

Shift from:

Grade <3 to ≥3

n/NAR (%)

Shift from:

Grade <4 to ≥4

n/NAR (%)

7-Study Dataset Through 24 Weeks of Assigned Treatment

Placebo (N=1184)

93/1092 (8.5)

14/1164 (1.2)

5/1171 (0.4)

2/1173 (0.2)

BARI 4 mg (N=1111)

374/1035 (36.1)a

58/1094 (5.3) a

12/1100 (1.1)

6/1100 (0.5)

4-Study Extended Datasetb

BARI 2 mg (N=479)

147/451 (32.6)

30/477 (6.3)

8/477 (1.7)

1/477 (0.2)

BARI 4 mg (N=479)

208/438 (47.5)c

63/470 (13.4)c

14/474 (3.0)

4/474 (0.8)

All BARI RA Datasetd

All BARI RA (N=3770)

1817/3384 (53.7)

450/3550 (12.7)

111/3560 (3.1)

27/3564 (0.8)

Abbreviations: BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number of patients at risk for specified abnormality; PYE = patient years of exposure; RA = rheumatoid arthritis.

a p=.001; Difference between BARI 4 mg and placebo.

b In the 4-study extended dataset through 13 February 2018, BARI 4-mg (N=479, PYE=698.6, median exposure=342 days, maximum exposure=2520 days) and BARI 2-mg group (N=479, PYE=675.6, median exposure=257 days, maximum exposure=1805 days).

c p=.001; Difference between BARI 4 mg and BARI 2 mg.

d All BARI RA dataset through 13 February 2018, (N=3770, PYE=10,127, median exposure=3.1 yrs, maximum exposure=6.9 yrs).

Adverse Events Related to Elevated Creatine Phosphokinase in Rheumatoid Arthritis Clinical Trials

There was no evidence that BARI treatment increased the risk of serious muscle-related AEs.1,3

Evaluation of elevations in CPK in the RA development program included a review of TEAEs using a query for “muscle symptoms.” The muscle symptoms query used a sponsor-defined MedDRA search criteria list that contained narrow scope terms from the rhabdomyolysis and myopathy standardized MedDRA query plus selected terms from the Musculoskeletal System Organ Class.1

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 2019.4,5

Events Leading to Permanent Discontinuation of Study Treatment

In the All BARI RA dataset, 6 patients (0.2%) permanently discontinued BARI treatment due to increased CPK.1

Additional Non-Serious Cases of Myopathy, Myositis, and Rhabdomyolysis

In the All BARI RA dataset, non-serious AEs observed included

  • myopathy in 7 (0.2%) patients

  • myositis in 7 (0.2%) patients, and

  • rhabdomyolysis in 2 (0.1%) patients.1

In the All BARI RA dataset, discontinuation from the study occurred in

  • 1 (0.0%) patient due to myopathy, and

  • 2 (0.1%) patients due to myositis.1

Information from the Label

Frequency for creatine phosphokinase increased > 5 x ULN is based on the pooled rheumatoid arthritis and atopic dermatitis clinical trials. In patients treated with baricitinib in the rheumatoid arthritis clinical trials, the frequency of those events was uncommon.6

In rheumatoid arthritis controlled studies, for up to 16 weeks, increases in CPK values were uncommon. Significant increases (> 5 x ULN) occurred in

  • 0.8 % of patients treated with baricitinib and

  • 0.3 % of patients treated with placebo.6

A dose relationship was observed with CPK elevations ≥ 5 x ULN of normal reported in 1.5 %, 0.8 % and 0.6 % of patients at 16 weeks in the 4 mg, 2 mg and placebo groups, respectively.6

In atopic dermatitis controlled studies, for up to 16 weeks, increases in CPK values were common and occurred in 3.3 %, 2.5 %, and 1.9 % of patients treated with baricitinib 4 mg, 2 mg, and placebo, respectively.6

Across indications, most cases were transient and did not require treatment discontinuation.6

In rheumatoid arthritis and atopic dermatitis clinical trials, there were no confirmed cases of rhabdomyolysis. Elevations of CPK were observed at 4 weeks and remained stable at a higher value than baseline thereafter including in the long-term extension study.6

References

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

2. Genovese MC, Smolen JS, Takeuchi 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

3. 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. J Rheumatol. 2019;46(1):7-18. http://dx.doi.org/10.3899/jrheum.171361

4. 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. https://ard.bmj.com/content/79/Suppl_1/642.1

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. Poster presented at: European League Against Rheumatism Virtual Congress; June 3-6, 2020.

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

Glossary

BARI = baricitinib

CPK = creatine phosphokinase

MedDRA = Medical Dictionary for Regulatory Activities

RA = rheumatoid arthritis

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.

Date of Last Review: May 27, 2020


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