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 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.2
Patients
were excluded from these phase 3 studies if they had an eGFR <40
mL/min/1.73 m2.2
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.2
Estimated
GFRs were calculated from serum creatinine using the Chronic Kidney
Disease Epidemiology Collaboration Creatinine 2009 equation.2,3
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 1.2
Table
1. Clinical Trial Criteria for Temporary Interruption and Resumption
of Study Treatment Based on eGFRa
in AD Clinical Trials2
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.
a
Based on serum creatinine.
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
Datasets2
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
Dataset2
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
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
Dataset2
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
Dataset2
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.2
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 × ULN2
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 1.2
See Table 2
for more details.
Table
2. CTCAE Grade Changes in Creatinine (umol/L)2
|
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.
d
p≤.05 vs BARI 2 mg.
Abnormal
High Laboratory Results
High
Serum Creatinine
A
high serum creatinine was defined as above the defined reference
range by age and sex.2
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).2
There
was no significant difference in high serum creatinine between BARI
2 mg and BARI 4 mg groups through 16 weeks and extended treatment.2
High
Serum Cystatin C
A
high serum cystatin C was defined as above the defined reference
range by age and sex.2
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%).2
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.2
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.2
Of
these 8 events, most were considered mild or moderate in severity
after medical review, and 5 were not considered related to study
drug.2
Table
3 provides more details on
renal-related TEAEs by safety dataset and treatment arms.