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Olumiant ® ▼ (baricitinib)
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Olumiant Summary of Product Characteristics (SmPC)
Olumiant® ▼ (baricitinib): Renal-Related Adverse Events and Analyte Changes in Atopic Dermatitis
In the atopic dermatitis clinical trials, small mean changes in serum creatinine and cystatin C with baricitinib treatment were not associated with renal dysfunction adverse events.
Baricitinib Label Information Related to Renal Impairment and Creatinine
Dosing Recommendations in Renal Impairment
Renal function was found to significantly affect baricitinib exposure.1
The recommended dose is 2 mg once daily in patients with creatinine clearance between 30 and 60 mL/min. Baricitinib is not recommended for use in patients with creatinine clearance < 30 mL/min.1
Creatinine
In rheumatoid arthritis, baricitinib induced a mean increase in serum creatinine levels of 3.8 µmol/L after two weeks of treatment, as compared to placebo, which remained stable thereafter during up to 104 weeks of treatment. This may be due to inhibition of creatinine secretion by baricitinib in the renal tubules.1
Consequently, estimates of the glomerular filtration rate based on serum creatinine may be slightly reduced, without actual loss of renal function or the occurrence of renal adverse events.1
In atopic dermatitis, baricitinib was associated with a decrease in cystatin C (also used to estimate glomerular filtration rate) of 0.1 mg/L at week 4, with no further decrease noted up to week 16.1
Renal Impairment in Atopic Dermatitis Clinical Trials
Dose Adjustments for Renal Impairment
In the BREEZE-AD clinical trial program, slight dose-dependent increases in serum creatinine were observed with baricitinib. These were not associated with increased risk of serious renal related AEs such as renal impairment/injury or renal failure.2
In the AD phase 3 studies with the highest dose of 4 mg, patients with an eGFR ≥40 and <60 mL/min/1.73 m2
received BARI 2 mg once daily if assigned to either the BARI 2 mg or BARI 4 mg treatment arms, and
received BARI 1 mg if assigned to the BARI 1 mg treatment arm.3
Patients were excluded from these phase 3 studies if they had an eGFR <40 mL/min/1.73 m2.3
In the AD phase 3 studies with the highest dose of BARI 2 mg (BREEZE-AD5 and BREEZE-AD6), patients with an eGFR <60 mL/min/1.73 m2 were excluded from the studies.3
Estimated GFRs were calculated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration Creatinine 2009 equation.3,4
Treatment Interruptions Due to Renal Impairment
In the AD phase 3 clinical trials, routine laboratory monitoring of serum creatinine to calculate eGFR was collected. Clinical trial criteria regarding study treatment interruption based on decreased eGFR are provided in Table 1.3
Table 1. Clinical Trial Criteria for Temporary Interruption and Resumption of Study Treatment Based on eGFRa in AD Clinical Trials3
|
Atopic Dermatitis Clinical Trials |
Study treatment was interrupted if |
Study treatment was resumed when |
|
BREEZE-AD1, BREEZE-AD2, BREEZE-AD3, BREEZE-AD4, and BREEZE-AD7 |
eGFR decreased to <40 mL/min/1.73 m2 in patients with a screening eGFR ≥60 mL/min/1.73 m2 |
eGFR increased to ≥50 mL/min/1.73 m2 |
|
eGFR decreased to <30 mL/min/1.73 m2 in patients with a screening eGFR ≥40 to <60 mL/min/1.73 m2 |
eGFR increased to ≥40 mL/min/1.73 m2 |
|
|
BREEZE-AD5 and BREEZ-AD6 |
eGFR decreased to <50 mL/min/1.73 m2 |
eGFR increased to ≥60 mL/min/1.73 m2 |
Abbreviations: AD = atopic dermatitis; eGFR = estimated glomerular filtration rate.
Integrated Safety Datasets Used to Evaluate Safety
The integrated datasets used to evaluate safety in the AD clinical trials are described in detail in Table 4
Mean Renal-Related Laboratory Changes
Mean Serum Creatinine Changes
In the AD clinical trial program, minor dose-dependent increases in serum creatinine were observed with BARI treatment; however, the changes were not considered clinically meaningful.2
Mean changes in serum creatinine from baseline to each measurement time point are provided in Figure 1 for the placebo-controlled period and Figure 2 for the BARI 2 mg and 4 mg extended dataset.
Figure 1. Mean Change in Serum Creatinine for AD Placebo-Controlled Datasets3
Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; Max = maximum; Min = minimum; PBO = placebo; PC = placebo-controlled; StdDev = standard deviation.
Figure 2. Mean Change in Serum Creatinine for AD BARI 2 mg vs 4 mg Extended Dataset3
Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; ext = extended; Max = maximum; Min = minimum; StdDev = standard deviation.
Mean Serum Cystatin C Changes
In the AD clinical trial program, there was a mean decrease in serum cystatin C in all treatment groups through week 12, with no further decrease through week 16. The mean changes were not associated with AEs of renal dysfunction.2,3
Mean changes in serum cystatin C from baseline to each measurement time point are provided in Figure 3 for the placebo-controlled period and Figure 4 for the BARI 2 mg and 4 mg extended dataset.
Figure 3. Mean Change in Serum Cystatin C for AD Placebo-Controlled Dataset3
Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; Max = maximum; Min = minimum; PBO = placebo; PC = placebo-controlled; StdDev = standard deviation.
Figure 4. Mean Change in Serum Cystatin C for AD BARI 2 mg vs 4 mg Extended Dataset3
Abbreviations: AD = atopic dermatitis; Avg = average; BARI = baricitinib; ext = extended; Max = maximum; Min = minimum; StdDev = standard deviation.
Renal Related Laboratory Adverse Events
CTCAE Grade Shifts in Creatinine
Categorical changes in creatinine values were assessed by determining the proportion of patients with a TE value above the ULN as well as the proportion of patients with a TE increase in CTCAE grades. Normal limits were defined according to
laboratory methodology
age, and
sex.3
CTCAE grade shifts are defined as:
Grade 0: (normal): ≤ULN
Grade 1: >ULN and ≤1.5 × ULN
Grade 2: >1.5 × ULN and ≤3 × ULN
Grade 3: >3 × ULN and ≤6 × ULN, and
Grade 4: >6 × ULN3
Through 16 weeks, a significantly higher proportion of patients had an increase in any CTCAE grade shift in creatinine in the
BARI 2 mg group than placebo group (6.2% vs 3.6%; p≤.01)
BARI 4 mg group than placebo group (8.4% vs 3.6%; p≤.001), and
BARI 4 mg group than BARI 2 mg group (8.4% vs 5.3%; p≤.05).
The majority of the shifts in all treatment groups were to Grade 1.3 See Table 2 for more details.
Table 2. CTCAE Grade Changes in Creatinine (umol/L)3
|
|
Any Grade Increase |
Increased to Grade ≥1 |
Increased to Grade ≥2 |
Increased to Grade ≥3 |
Increased to Grade ≥4 |
|
BARI 2 mg placebo-controlleda, n/NAR (%) |
|||||
|
Placebo, n=889 |
31/871 (3.6) |
31/821 (3.8) |
1/870 (0.1) |
1/871 (0.1) |
0/871 |
|
BARI 2 mg, n=721 |
44/709 (6.2)b |
42/661 (6.4)b |
3/708 (0.4) |
0/709 |
0/709 |
|
BARI 4 mg placebo-controlleda, n /NAR (%) |
|||||
|
Placebo, n=743 |
26/729 (3.6) |
26/693 (3.8) |
1/728 (0.1) |
1/729 (0.1) |
0/729 |
|
BARI 4 mg, n=489 |
41/488 (8.4)c |
40/468 (8.5)c |
1/488 (0.2) |
0/488 |
0/488 |
|
BARI 2 mg vs 4 mga, n/NAR (%) |
|||||
|
BARI 2 mg, n=576 |
30/570 (5.3) |
30/538 (5.6) |
1/569 (0.2) |
0/570 |
0/570 |
|
BARI 4 mg, n=489 |
41/488 (8.4)d |
40/468 (8.5) |
1/488 (0.2) |
0/488 |
0/488 |
|
BARI 2 mg vs 4 mg extended, n/NAR (%) |
|||||
|
BARI 2 mg, n=576 |
53/570 (9.3) |
53/538 (9.9) |
2/569 (0.4) |
0/570 |
0/570 |
|
BARI 4 mg, n=489 |
56/488 (11.5) |
55/468 (11.8) |
1/488 (0.2) |
0/488 |
0/488 |
|
All BARI AD, n/NAR (%) |
|||||
|
All doses, N=2531 |
246/2497 (9.9) |
240/2312 (10.4) |
9/2495 (0.4) |
1/2497 (0.0) |
1/2497 (0.0) |
Abbreviations: AD = atopic dermatitis; BARI = baricitinib; CTCAE = Common Terminology Criteria for Adverse Events; NAR = number at risk.
a Data through 16-week placebo-controlled period.
b p≤.01 vs placebo.
c p≤.001 vs placebo.
Abnormal High Laboratory Results
High Serum Creatinine
A high serum creatinine was defined as above the defined reference range by age and sex.3
Through 16 weeks, compared to placebo, a significantly higher proportion of patients had a TE high serum creatinine in the
BARI 2 mg group (6.4% vs 3.8%; p≤.01), and
BARI 4 mg group (8.5% vs 3.8%; p≤.001).3
There was no significant difference in high serum creatinine between BARI 2 mg and BARI 4 mg groups through 16 weeks and extended treatment.3
High Serum Cystatin C
A high serum cystatin C was defined as above the defined reference range by age and sex.3
Through 16 weeks, TE high serum cystatin C was
significantly lower in the BARI 2 mg group than placebo (2.9% vs 7.9%; p≤.001), and
not different in the BARI 4 mg group and placebo group (4.5% vs 8.3%).3
There was no significant difference in high serum cystatin C between BARI 2 mg and BARI 4 mg groups through 16 weeks and extended treatment.3
Renal-Related Adverse Events
Of the 2531 patients treated with BARI, renal-related TEAEs were reported in 39 (1.5%, IR=1.7) patients. Events of most interest included
4 (IR=0.2) cases of renal impairment
3 (IR=0.1) cases of acute kidney injury, and
1 (IR=0.0) case of renal failure.3
Of these 8 events, most were considered mild or moderate in severity after medical review, and 5 were not considered related to study drug.3
Table 3 provides more details on renal-related TEAEs by safety dataset and treatment arms.
Table 3. Renal-Related Treatment Emergent Adverse Events3
|
|
|
|
|
|
|
|
|
|
|
|
|
BARI
2 mg Placebo-Controlleda |
BARI
4 mg Placebo-Controlleda |
BARI
2 mg vs 4 mga |
BARI
2 mg vs 4 mg ext |
All
BARI AD |
||||
|
|
Placebo |
BARI
2 mg |
Placebo |
BARI
4 mg |
BARI
2 mg |
BARI
4 mg |
BARI
2 mg |
BARI
4 mg |
All
Doses |
|
Renal and urinary disorders SOC |
4 (0.6) |
3 (0.3) |
3 (0.5) |
9 (1.7)c |
2 (0.2) |
9 (1.7)d |
9 (1.4) [2.1] |
12 (2.2) [2.6] |
39 (1.5 ) [1.7] |
|
Serious AE |
0 |
0 |
0 |
0 |
0 |
0
|
0 |
0 |
2 (0.1) [0.1]e |
|
Led to temp int |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.2] |
2 (0.1) [0.1] |
|
Led to perm D/C |
0 |
0 |
0 |
1 (0.2) |
0 |
1 (0.2) |
0 |
1 (0.2) [0.2] |
1 (0.0) [0.0] |
Abbreviations: AD = atopic dermatitis; adj = adjusted; AE = adverse event; BARI = baricitinib; ext = extended; IR = incidence rate; perm D/C = permanent discontinuation; SOC = system organ class; temp int = temporary interruption.
a Data through 16-week placebo-controlled period.
b For 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 (eg, 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.
c p≤.05 vs placebo.
d p≤.05 vs BARI 2 mg.
e Includes 1 patient with 2 events (calculus urinary and renal colic) and 1 patient with 1 event (renal failure).
Potential Role of JAK Inhibition in Tubular Secretion of Creatinine
Baricitinib is a selective, and reversible inhibitor of the JAK family of protein tyrosine kinases, specifically JAK1 and JAK2.5
In vitro experiments using cell systems expressing individual or multiple renal transporters indicated that BARI may competitively inhibit tubular secretion of creatinine by inhibiting OCT2-mediated uptake of creatinine as well as MATE1/MATE2-K-mediated efflux of creatinine. The pattern of small increases in creatinine seen rapidly after initiation of BARI is consistent with such a mechanism.3,6
The mechanism of the small, reversible, and dose-dependent increases in serum creatinine observed with BARI treatment has not been fully characterized.3
Table 4. Integrated Analysis Datasets Used to Evaluate Safety in Atopic Dermatitis Clinical Trials2,3
|
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.
1. Olumiant [summary of product characteristics]. Eli Lilly Nederland B.V., The Netherlands.
2. Bieber 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. Published online September 14, 2020. https://doi.org/10.1111/jdv.16948
3. Data on file, Eli Lilly and Company and/or one of its subsidiaries.
4. Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763564/
5. 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
6. Zhang Y, Warren MS, Zhang X, et al. Impact on creatinine renal clearance by the interplay of multiple renal transporters: a case study with INCB039110. Drug Metab Dispos. 2015;43(4):485-489. http://dx.doi.org/10.1124/dmd.114.060673
Glossary
AD = atopic dermatitis
AE = adverse event
BARI = baricitinib
CTCAE = Common Terminology Criteria for Adverse Events
eGFR = estimated glomerular filtration rate
IR = incidence rate
JAK = Janus kinase
MATE = multidrug and toxin extrusion protein
OCT = organic cation transporter
TE = treatment-emergent
TEAE = treatment-emergent adverse event
ULN = upper limit of normal
▼ 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: January 29, 2021
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