TRESIBA
®
(insulin degludec injection)
5
Figure 1: Structural Formula of TRESIBA
®
Gly
Ile
Val Glu Gln Cys Cys Thr Ser
Ile Cys Ser Leu Tyr Gln Leu Glu Asn Tyr Cys Asn
Phe Val Asn Gln His Leu Cys Gly Ser His Leu Val Glu Ala Leu Tyr Leu Val Cys Gly Glu Arg Gly Phe Phe Tyr Thr Pro
H
OH
H
H
N
B29
O
OH
HN
O
NH
(CH
2
)
14
O
HO
O
HO
O
A1
A10
A20
B1
B10
B20
TRESIBA
®
is a sterile, aqueous, clear, and colorless solution that contains insulin degludec 100
units/mL (U-100) or 200 units/mL (U-200).
For the 100 units/mL solution, each mL contains 100 units (600 nmol) of insulin degludec and
glycerol (19.6 mg), metacresol (1.72 mg), phenol (1.50 mg), zinc (32.7 mcg), and Water for
Injection, USP.
For the 200 units/mL solution, each mL contains 200 units (1200 nmol) of insulin degludec
and glycerol (19.6 mg), metacresol (1.72 mg), phenol (1.50 mg), zinc (71.9 mcg), and Water for
Injection, USP.
TRESIBA
®
has a pH of approximately 7.6. Hydrochloric acid or sodium hydroxide may be added
to adjust pH.
12
CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
The primary activity of insulin, including TRESIBA
®
, is regulation of glucose metabolism. Insulin
and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by
skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits
lipolysis and proteolysis, and enhances protein synthesis. TRESIBA
®
forms multi-hexamers
when injected into the subcutaneous tissue resulting in a subcutaneous insulin degludec depot.
The protracted time action profile of TRESIBA
®
is predominantly due to delayed absorption of
insulin degludec from the subcutaneous tissue to the systemic circulation and to a lesser extent
due to binding of insulin-degludec to circulating albumin.
12.2 Pharmacodynamics
The glucose-lowering effect of TRESIBA
®
after 8 days of once-daily dosing was measured in a
euglycemic glucose clamp study enrolling 21 patients with type 1 diabetes. Figure 2 shows the
pharmacodynamic effect of TRESIBA
®
over time following 8 once-daily subcutaneous injections
of 0.4 U/kg of TRESIBA
®
in patients with type 1 diabetes.
Figure 2: Mean GIR Profile for 0.4 units/kg Dose of TRESIBA
®
(Steady State) in
Patients with Type 1 Diabetes Mellitus
3
2
1
0
GIR
0
6
12
18
24
Time since injection (hours)
Treatment
IDeg 0.4 U/kg
Shaded area represents the 24 hr interval
30
36
42
The mean maximum glucose lowering effect (GIR
max
) of a 0.4 units/kg dose of TRESIBA
®
was
2.0 mg/kg/min, which was observed at a median of 12 hours post-dose. The glucose lowering
effect of TRESIBA
®
lasted at least 42 hours after the last of 8 once-daily injections.
In patients with type 1 diabetes mellitus, the steady-state, within subjects, day-to-day variability
in total glucose lowering effect was 20% with TRESIBA
®
(within-subject coefficient of variation
for AUC
GIR,
τ
,SS
).
The total glucose-lowering effect of TRESIBA
®
over 24 hours measured in a euglycemic clamp
study after 8 days of once-daily administration in patients with type 1 diabetes increases
approximately in proportion to the dose for doses between 0.4 units/kg to 0.8 units/kg.
The total glucose-lowering effect of 0.4 units/kg of TRESIBA
®
U-100 and 0.4 units/kg of
TRESIBA
®
U-200, administered at the same dose, and assessed over 24 hours in a euglycemic
clamp study after 8 days of once-daily injection was comparable.
12.3 Pharmacokinetics
Absorption
In patients with type 1 diabetes, after 8 days of once daily subcutaneous dosing with 0.4 units/kg
of TRESIBA
®
, maximum degludec concentrations of 4472 pmol/L were attained at a median of 9
hours (t
max
). After the first dose of TRESIBA
®
, median onset of appearance was around one hour.
Total insulin degludec concentration (i.e., exposure) increased in a dose proportional manner
after subcutaneous administration of 0.4 units/kg to 0.8 units/kg TRESIBA
®
. Total and maximum
insulin degludec exposure at steady state are comparable between TRESIBA
®
U-100 and
TRESIBA
®
U-200 when each is administered at the same units/kg dose.
Insulin degludec concentration reached steady state levels after 3-4 days of TRESIBA
®
adminis-
tration
[see Dosage and Administration (2.2)]
.
Distribution
The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of
>99% in human plasma. The results of the
in vitro
protein binding studies demonstrate that there
is no clinically relevant interaction between insulin degludec and other protein bound drugs.
Elimination
The half-life after subcutaneous administration is determined primarily by the rate of absorption
from the subcutaneous tissue. On average, the half-life at steady state is approximately 25
hours independent of dose. Degradation of TRESIBA
®
is similar to that of insulin human; all
metabolites formed are inactive. The mean apparent clearance of insulin degludec is 0.03 L/kg
(2.1 L/h in 70 kg individual) after single subcutaneous dose of 0.4 units/kg.
Specific Populations
Pediatrics-
Population pharmacokinetic analysis was conducted for TRESIBA
®
using data from 199 pediatric
subjects (1 to <18 years of age) with type 1 diabetes. Body weight was a significant covariate
affecting the clearance of TRESIBA
®
. After adjusting for body weight, the total exposure of
TRESIBA
®
at steady state was independent of age.
Geriatrics-
Pharmacokinetic and pharmacodynamic response of TRESIBA
®
was compared in 13 younger
adult (18−35 years) and 14 geriatric (
≥
65 years) subjects with type 1 diabetes following two
6-day periods of once-daily subcutaneous dosing with 0.4 units/kg dose of TRESIBA
®
or insulin
glargine. On average, the pharmacokinetic and pharmacodynamic properties of TRESIBA
®
at
steady-state were similar in younger adult and geriatric subjects, albeit with greater between
subject variability among the geriatric subjects.
Gender-
The effect of gender on the pharmacokinetics of TRESIBA
®
was examined in an across-trial
analysis of the pharmacokinetic and pharmacodynamic studies conducted using unit/kg doses
of TRESIBA
®
. Overall, there were no clinically relevant differences in the pharmacokinetic
properties of insulin degludec between female and male subjects.
Obesity-
The effect of BMI on the pharmacokinetics of TRESIBA
®
was explored in a cross-trial analysis of
pharmacokinetic and pharmacodynamic studies conducted using unit/kg doses of TRESIBA
®
.
For subjects with type 1 diabetes, no relationship between exposure of TRESIBA
®
and BMI was
observed. For subjects with type 1 and type 2 diabetes a trend for decrease in glucose-lowering
effect of TRESIBA
®
with increasing BMI was observed.
Race and Ethnicity-
TRESIBA
®
has been studied in a pharmacokinetic and pharmacodynamic study in Black or
African American subjects not of Hispanic or Latino origin (n=18), White subjects of Hispanic
or Latino origin (n=22) and White subjects not of Hispanic or Latino origin (n=23) with type
2 diabetes mellitus conducted using unit/kg doses of TRESIBA
®
. There were no statistically
significant differences in the pharmacokinetic and pharmacodynamic properties of TRESIBA
®
between the racial and ethnic groups investigated.
Pregnancy-
The effect of pregnancy on the pharmacokinetics and pharmacodynamics of TRESIBA
®
has not
been studied
[see Use in Specific Populations (8.1)].
Renal Impairment-
TRESIBA
®
pharmacokinetics was studied in 32 subjects (n=4-8/group) with normal or impaired
renal function/end-stage renal disease following administration of a single subcutaneous dose
(0.4 units/kg) of TRESIBA
®
. Renal function was defined using creatinine clearance (Cl
cr
) as
follows:
≥
90 mL/min (normal), 60-89 mL/min (mild), 30-59 mL/min (moderate) and <30 mL/
min (severe). Subjects requiring dialysis were classified as having end-stage renal disease
(ESRD). Total (AUC
IDeg,0-120h,SD
) and peak exposure of TRESIBA
®
were on average about
10-25% and 13-27% higher, respectively in subjects with mild to severe renal impairment
except subjects with ESRD who showed similar exposure as compared to subjects with normal
renal function. No systematic trend was noted for this increase in exposure across different renal
impairment subgroups. Hemodialysis did not affect clearance of TRESIBA
®
(CL/F
IDeg,SD
) in
subjects with ESRD
[see Use in Specific Populations (8.6)]
.
Hepatic Impairment-
TRESIBA
®
has been studied in a pharmacokinetic study in 24 subjects (n=6/group) with
normal or impaired hepatic function (mild, moderate, and severe hepatic impairment) following
administration of a single subcutaneous dose (0.4 units/kg) of TRESIBA
®
. Hepatic function was
defined using Child-Pugh Scores ranging from 5 (mild hepatic impairment) to 15 (severe hepatic
impairment). No differences in the pharmacokinetics of TRESIBA
®
were identified between
healthy subjects and subjects with hepatic impairment
[see Use in Specific Populations (8.7)]
.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the
carcinogenic potential of insulin degludec. In a 52-week study including human insulin (NPH
insulin) as comparator (6.7 units/kg/day), Sprague-Dawley rats were dosed subcutaneously
with insulin degludec at 3.3, 6.7, and 10 units/kg/day, resulting in 5 times the human exposure
(AUC) when compared to a human subcutaneous dose of 0.75 units/kg/day. Human insulin was
dosed at 6.7 units/kg/day. No treatment-related increases in incidences of hyperplasia, benign
or malignant tumors were recorded in female mammary glands from rats dosed with insulin
degludec and no treatment related changes in the female mammary gland cell proliferation
were found using BrdU incorporation. Further, no treatment related changes in the occurrence
of hyperplastic or neoplastic lesions were seen in other tissues in animals dosed with insulin
degludec when compared to vehicle or human insulin.
Genotoxicity testing of insulin degludec was not performed.
In a combined fertility and embryo-fetal study in male and female rats, treatment with insulin
degludec up to 21 units/kg/day (approximately 5 times the human subcutaneous dose of 0.75
units/kg/day, based on units/body surface area) prior to mating and in female rats during
gestation had no effect on mating performance and fertility.
14
CLINICAL STUDIES
The efficacy of TRESIBA
®
administered once-daily either at the same time each day or at any time
each day in patients with type 1 diabetes and used in combination with a mealtime insulin was
evaluated in three randomized, open-label, treat-to-target, active-controlled trials in adults and
one randomized, open-label, treat-to-target, active-controlled trial in pediatric patients 1 year of
