Olumiant ® (baricitinib)

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What is the incidence of infections with Olumiant® (baricitinib) treatment in the atopic dermatitis clinical development program?

The most frequent infections reported in patients treated with baricitinib during atopic dermatitis clinical trials were nasopharyngitis, upper respiratory infection, oral herpes, influenza, folliculitis and urinary tract infections.

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UK_cFAQ_BAR122B_INFECTION_AD
en-GB

Infections in atopic dermatitis clinical trials

Infections were defined using Medical Dictionary for Regulatory Activities (MedDRA) preferred terms in the infections and infestations system organ class. Infections were defined as serious infections if they met the International Conference on Harmonisation criteria for a serious adverse event (AE).1,2

Placebo-Controlled Period

Overall Infections

Through 16 weeks, the proportion of patients with a treatment-emergent infection was

Serious Infections

Through 16 weeks, the proportion of patients with a treatment-emergent serious infection was not significantly different between the BARI 2 mg and BARI 4 mg groups compared to placebo groups (see Summary of Infections in the Atopic Dermatitis Clinical Trials).2

All baricitinib-treated patients with extended data

Overall Infections

Of the 2531 patients treated with all BARI doses in the atopic dermatitis (AD) clinical trials, 1272 (IR=91.7) patients had a treatment-emergent infection.1 The most frequent infections reported were

  • nasopharyngitis (n=439, IR=22.0)
  • upper respiratory tract infection (n=160, IR=7.2)
  • oral herpes (n=110, n=4.9)
  • influenza (n=100, n=4.4)
  • herpes simplex (n=91, IR=4.0)
  • folliculitis (n=72, IR=3.2), and
  • urinary tract infection (n=72, IR=3.2).1,2

See Summary of Infections in the Atopic Dermatitis Clinical Trials for more information including the incidence of skin infections requiring antibiotics.

Of the 137 infections that led to temporary interruption of BARI, the most frequent were HZ (n=27) and herpes simplex (n=31).2

Serious Infections

Of the infections in patients treated with BARI, 48 (IR=2.1) were considered serious.1 The most frequent serious infections reported were

  • eczema herpeticum (n=11, IR=0.5)
  • cellulitis (n=6, IR=0.3), and
  • pneumonia (n=3, IR=0.1).1
Summary of Infections in the Atopic Dermatitis Clinical Trials3

 

 

 

 

 

 

 

 

 

 

 

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]c


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

Infections

252 (28.4)

251 (34.4)d

216 (24.2)

183 (31.5)e

212 (29.8)

183 (31.5)

294 (42.5) [115.4]

281 (48.9) [117.4]f

1272 (50.3) [91.7]

Serious infections

6 (0.7)

4 (0.5)

5 (0.6)

3 (0.6)

3 (0.4)

3 (0.6)

8 (0.9) [1.5]

13 (2.5) [3.0]

48 (1.9) [2.1]

Led to temp int

6 (0.6)

17 (2.2)d

4 (0.4)

15 (2.7)g

17 (2.2)

15 (2.7)

32 (4.2) [6.8]

31 (5.6) [7.3]

137 (5.4) [6.1]

Led to perm D/C

3 (0.3)

2 (0.3)

2 (0.2)

2 (0.4)

2 (0.3)

2 (0.4)

5 (0.6) [0.9]

6 (1.2) [1.5]

20 (0.8) [0.9]

Skin infections requiring antibiotics

46 (5.4)

37 (5.5)

38 (4.4)

18 (3.4)

31 (4.8)

18 (3.4)

31 (4.8) [7.5]

18 (3.4) [4.3]

75 (3.1) [3.4]

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; ext = extended IR = incidence rate; perm D/C = permanent discontinuation; temp int = temporary interruption.

aData through 16-week placebo-controlled period.

bFor 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 (example 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. 

cIncidence 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.

dp≤.05 vs placebo

ep≤.01 vs placebo.

fp≤.01 vs BARI 2 mg.

gp≤.001 vs placebo.

Lymphopenia or neutropenia and infection

Baricitinib Label Information Related to Lymphocytes and Neutrophils Counts

Absolute Neutrophil Count (ANC) < 1 x 109 cells/L and Absolute Lymphocyte Count (ALC) < 0.5 x 109 cells/L were reported in clinical trials.4

Treatment should not be initiated, or should be temporarily interrupted, in patients with an

  • ANC < 1 x 109 cells/L, or
  • ALC < 0.5 x 109 cells/L 

observed during routine patient management.4

Association Between Infection and Neutropenia or Lymphopenia

To evaluate the association between infection and neutropenia or lymphopenia, the frequency of infections was analyzed by patient subgroups defined by the worst CTCAE grades of neutropenia and lymphopenia. For this analysis, no statistical comparison was provided. See results in  Treatment-Emergent Infections by Worst CTCAE Grade for Lymphopenia in Atopic Dermatitis Clinical Trials and Treatment-Emergent Infections by Worst CTCAE Grade for Neutropenia in Atopic Dermatitis Clinical Trials.2

 Treatment-Emergent Infections by Worst CTCAE Grade for Lymphopenia in Atopic Dermatitis Clinical Trials3

 

 

 

 

 

 

 

 

 

 

Lymphopenia Grades and Infection Categories

BARI 2 mg Placebo-Controlled

BARI 4 mg Placebo-Controlled

BARI 2 mg vs 4 mg

BARI 2 mg vs 4 mg ext

All BARI AD

Placebo
n=872

BARI 2 mg
n=708

Placebo
n=730

BARI 4 mg
n=487

BARI 2 mg
n=570

BARI 4 mg
n=487

BARI 2 mg
n=570

BARI 4 mg
n=487

All doses
N=2498

Patients with ≥1 TE infection
n-infection [serious]/n-Grade (adj %)a
b

Grade 0 (≥1.1 billion cells/L)

198 [3]
/694 (28.9)

192 [3]
/561 (33.2)

165 [3]
/582 (23.9)

135 [3]
/397 (28.3)

162 [2]
/453 (28.5)

135 [3]
/397 (28.3)

209 [5]
/410 (42.2)

189 [9]
/345 (46.4)

882 [33]
/1801 (49.0)

Grade 1 (<1.1 and ≥0.8 billion cells/L)

40 [1]
/140 (28.0)

46 [1]
/122 (37.8)

39 [1]
/118 (27.2)

39 [0]
/72 (46.2)

40 [1]
/101 (33.0)

39 [0]
/72 (46.2)

70 [2]
/136 (43.4)

67 [4]
/105 (53.7)

291 [10]
/545 (53.4)

Grade 2 (<0.8 and ≥0.5 billion cells/L)

14 [2]
/36 (29.1)

12 [0]
/24 (52.1)

12 [1]
/29 (24.2)

7 [0]
/15 (42.3)

9 [0]
/16 (45.8)

7 [0]
/15 (42.3)

14 [1]
/24 (55.5)

23 [0]
/33 (66.5)

89 [4]
/140 (63.6)

Grade 3 (<0.5 and ≥0.2 billion cells/L)

0/2

0/1 

0/1

2[0]
/3 (24.2)

0/0

2[0]
/3 (24.2)

0/0

2 [0]
/4 (24.2)

4 [0]
/12 (33.3)

Grade 4 (<0.2 billion cells/L)

0/0

0/0

0/0

0/0

0/0

0/0

0/0

0/0

0/0

Abbreviations: AD = atopic dermatitis; adj = adjusted; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; TE = treatment-emergent.

aAll BARI AD dataset is presented as percentage, all others datasets are presented as adjusted percentage.

bFor 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 (example 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. 

Treatment-Emergent Infections by Worst CTCAE Grade for Neutropenia in Atopic Dermatitis Clinical Trials3











Neutropenia Grades and Infection Categories

BARI 2 mg Placebo-Controlled

BARI 4 mg Placebo-Controlled

BARI 2 mg vs 4 mg

BARI 2 mg vs 4 mg ext

All BARI AD

Placebo
n=872

BARI 2 mg
n=708

Placebo
n=730

BARI 4 mg
n=487

BARI 2 mg
n=570

BARI 4 mg
n=487

BARI 2 mg
n=570

BARI 4 mg
n=487

All doses
N=2498

Patients with ≥1 TE infection
n-infection [serious]/n-Grade (adj %)a
b

Grade 0 (≥2 billion cells/L)

234 [6]
/819 (28.5)

228 [3]
/645 (34.8)

201 [5]
/690 (24.2)

158 [2]
/427 (31.0)

192 [2]
/521 (29.9)

158 [2]
/427 (31.0)

260 [7]
/504 (42.7)

228 [12]
/397 (48.9)

1091 [44]
/2147 (50.8)

Grade 1 (<2 and ≥1.5 billion cells/L)

15 [0]
/44 (34.1)

18 [1]
/48 (34.8)

12 [0]
/34 (29.0)

18 [0]
/45 (29.4)

17 [1]
/41 (32.4)

18 [0]
/45 (29.4)

27 [1]
/52 (42.0)

37 [0]
/63 (48.1)

128 [1]
/254 (50.4)

Grade 2 (<1.5 and ≥1.0 billion cells/L)

3 [0]
/9 (36.0)

4 [0]
/14 (13.8)

3 [0]
/6 (36.0)

6 [1]
/14 (40.0)

2 [0]
/7 (8.9)

6 [1]
/14 (40.0)

6 [1]
/13 (33.9)

14 [1]
/24 (51.1)

44 [2]
/88 (50.0)

Grade 3 (<1.0 and ≥0.5 billion cells/L)

0/0

0/1

0/0

1 [0]
/1 (12.7)

0/0

1 [0]
/1 (12.7)

0/1

2 [0]
/3 (21.6)

3 [0]
/9 (33.3)

Grade 4 (<0.5 billion cells/L)

0/0

0/0

0/0

0/0

0/0

0/0

0/0

0/0

0/0

Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; TE = treatment-emergent.

aAll BARI AD dataset is presented as percentage, all others datasets are presented as adjusted percentage.

bFor 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 (example 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. 

Baricitinib label information related to infections

Warnings and Precautions

Baricitinib is associated with an increased rate of infections such as upper respiratory tract infections compared to placebo. In rheumatoid arthritis clinical studies, in treatment naïve patients, combination with methotrexate resulted in increased frequency of infections compared to baricitinib monotherapy.4

The risks and benefits of treatment with baricitinib should be carefully considered prior to initiating therapy in patients with active, chronic or recurrent infections.4

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.4

Adverse Drug Reactions in Atopic Dermatitis

The frequencies of adverse reactions are based on integrated data from clinical trials and/or postmarketing setting across

  • rheumatoid arthritis, 
  • atopic dermatitis, and
  • alopecia areata

indications unless stated otherwise.4 

Infections such as 

  • upper respiratory tract infections (16.9 %) 
  • herpes simplex (3.2 %), and
  • urinary tract infections (2.9 %)

belong to the most commonly reported adverse drug reactions with baricitinib.4

In the integrated data from rheumatoid arthritis, atopic dermatitis and alopecia areata clinical trials, most infections were mild to moderate in severity.4

Frequency of herpes zoster was very rare in atopic dermatitis.

In atopic dermatitis clinical trials, there were less skin infections requiring antibiotic treatment with baricitinib than with placebo.4

The incidence of serious infections with baricitinib was similar to placebo.4

  • The incidence of serious infections remained stable during long term exposure.
  • The overall incidence rate of serious infections in the clinical trial programme was 2.1 per 100 patient-years in atopic dermatitis.

Integrated safety datasets table

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials describes in more detail the integrated safety datasets used to evaluate infections.

Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials1,2

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 section 4.2 of the Olumiant Summary of Product Characteristics for approved dosage.

References

1Bieber T, Thyssen JP, Reich K, et al. Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials. J Eur Acad Dermatol Venereol. 2021;35(2):476-485. https://doi.org/10.1111/jdv.16948

2Data on file, Eli Lilly and Company and/or one of its subsidiaries.

3Data on file, Eli Lilly and Company and/or one of its subsidiaries.

4Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.

Date of Last Review: 18 February 2021


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