TRESIBA
®
(insulin degludec injection)
4
6.2 Immunogenicity
As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form.
The detection of antibody formation is highly dependent on the sensitivity and specificity of the
assay and may be influenced by several factors such as: assay methodology, sample handling,
timing of sample collection, concomitant medication, and underlying disease. For these reasons,
comparison of the incidence of antibodies to TRESIBA
®
with the incidence of antibodies in other
studies or to other products may be misleading.
In a 52-week study of adult insulin-experienced type 1 diabetes patients, 68.9% of patients who
received TRESIBA
®
were positive at baseline for anti-insulin degludec antibodies and 12.3%
of the patients developed anti-insulin degludec antibodies at least once during the study. In a
52-week study of pediatric insulin-experienced type 1 diabetes patients, 84.1% of patients who
received TRESIBA
®
were positive at baseline for anti-insulin degludec antibodies and 5.8% of
patients developed anti-insulin degludec antibodies at least once during the study. In a 52-week
study of adult insulin-naïve type 2 diabetes patients, 1.7% of patients who received TRESIBA
®
were positive at baseline for anti-insulin degludec antibodies and 6.2% of patients developed
anti-insulin degludec antibodies at least once during the study. In these trials, between 96.7%
and 99.7% of patients who were positive for anti-insulin degludec antibodies were also positive
for anti-human insulin antibodies.
7
DRUG INTERACTIONS
Table 5 includes clinically significant drug interactions with TRESIBA
®
.
Table 5: Clinically Significant Drug Interactions with TRESIBA
®
Drugs That May Increase the Risk of Hypoglycemia
Drugs:
Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking
agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors,
pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin analogs
(e.g., octreotide), and sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4
inhibitors, SGLT-2 inhibitors.
Intervention:
Dose reductions and increased frequency of glucose monitoring may be
required when TRESIBA
®
is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of TRESIBA
®
Drugs:
Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids,
danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives,
phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors,
somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline),
and thyroid hormones.
Intervention:
Dose increases and increased frequency of glucose monitoring may be required
when TRESIBA
®
is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of
TRESIBA
®
Drugs:
Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause
hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:
Dose adjustment and increased frequency of glucose monitoring may be
required when TRESIBA
®
is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:
Beta-blockers, clonidine, guanethidine, and reserpine
Intervention:
Increased frequency of glucose monitoring may be required when TRESIBA
®
is
co-administered with these drugs.
8
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
There are no available data with TRESIBA
®
or insulin degludec in pregnant women to inform
a drug-associated risk for major birth defects and miscarriage. There are risks to the mother
and fetus associated with poorly controlled diabetes in pregnancy
[see Clinical Considerations]
.
Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organo-
genesis. Pre-and post-implantation losses and visceral/skeletal abnormalities were observed
in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of 0.75 U/
kg/day. These effects were similar to those observed in rats administered human insulin (NPH)
[see Data]
.
The estimated background risk of major birth defects is 6-10% in women with pre-gestational
diabetes with an HbA
1c
>7 and has been reported to be as high as 20-25% in women with
an HbA
1c
>10. The estimated background risk of miscarriage for the indicated population is
unknown. In the U.S. general population, the estimated background risk of major birth defects
and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.
Clinical Considerations
Disease-associated maternal and/or embryo/fetal risk
Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis,
pre-eclampsia, spontaneous abortions, preterm delivery, stillbirth and delivery complications.
Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and
macrosomia related morbidity.
Data
Animal Data
Insulin degludec was investigated in studies covering fertility, embryo-fetal development and
pre- and post-natal development in rats and during the period of embryo-fetal development
in rabbits. Human insulin (NPH insulin) was included as comparator. In these studies insulin
degludec caused pre- and post-implantation losses and visceral/skeletal abnormalities when
given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5
times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose
of 0.75 U/kg/day. Overall, the effects of insulin degludec were similar to those observed with
human insulin, which were probably secondary to maternal hypoglycemia.
8.2 Lactation
Risk Summary
There are no data on the presence of insulin degludec in human milk, the effects on the breastfed
infant, or the effects on milk production. Insulin degludec is present in rat milk
[see Data]
.
The developmental and health benefits of breastfeeding should be considered along with the
mother’s clinical need for TRESIBA
®
and any potential adverse effects on the breastfed infant
from TRESIBA
®
or from the underlying maternal condition.
Data
In lactating rats, insulin degludec was present in milk at a concentration lower than that in plasma.
8.4 Pediatric Use
The safety and effectiveness of TRESIBA
®
to improve glycemic control in type 1 and type 2
diabetes mellitus have been established in pediatric patients 1 year of age and older. The safety
and effectiveness of TRESIBA
®
have not been established in pediatric patients less than 1 year
old.
The use of TRESIBA
®
in pediatric patients 1 year of age and older with type 1 and type 2
diabetes mellitus is supported by evidence from an adequate and well-controlled study and a
pharmacokinetic study (studies included pediatric patients 1 year of age and older with type
1 diabetes mellitus)
[see Clinical Pharmacology (12.3) and Clinical Studies (14.2)]
. The use of
TRESIBA
®
in pediatric patients 1 year of age and older with type 2 diabetes mellitus is also
supported by evidence from adequate and well-controlled studies in adults with type 2 diabetes
mellitus
[see Clinical Studies (14.3)]
.
In pediatric patients 1 year of age and older already on insulin therapy, start TRESIBA
®
at a
reduced dose to minimize the risk of hypoglycemia
[see Dosage and Administration (2.4)]
.
8.5 Geriatric Use
In controlled clinical studies
[see Clinical Studies (14)]
a total of 77 (7%) of the 1102 TRESIBA
®
-
treated patients with type 1 diabetes were 65 years or older and 9 (1%) were 75 years or older.
A total of 670 (25%) of the 2713 TRESIBA
®
-treated patients with type 2 diabetes were 65 years
or older and 80 (3%) were 75 years or older. Differences in safety or effectiveness were not
suggested in subgroup analyses comparing subjects older than 65 years to younger subjects.
In the safety outcomes trial (DEVOTE), a total of 1983 (52%) of the 3818 TRESIBA
®
-treated
patients with type 2 diabetes were 65 years or older and 381 (10%) were 75 years or older.
Differences in safety or effectiveness were not observed in these subgroup analyses.
Nevertheless, greater caution should be exercised when TRESIBA
®
is administered to geriatric
patients since greater sensitivity of some older individuals to the effects of TRESIBA
®
cannot be
ruled out. The initial dosing, dose increments, and maintenance dosage should be conservative
to avoid hypoglycemia. Hypoglycemia may be more difficult to recognize in the elderly.
8.6 Renal Impairment
In clinical studies
[see Clinical Studies (14)]
a total of 75 (7%) of the 1102 TRESIBA
®
-treated
patients with type 1 diabetes had an eGFR less than 60 mL/min/1.73 m
2
and 1 (0.1%) had an
eGFR less than 30 mL/min/1.73 m
2
. A total of 250 (9%) of the 2713 TRESIBA
®
-treated patients
with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m
2
and no subjects had an eGFR
less than 30 mL/min/1.73 m
2
.
In the safety outcomes trial (DEVOTE), a total of 1429 (37.4%) of the 3818 TRESIBA
®
-treated
patients with type 2 diabetes had an eGFR less than 60 mL/min/1.73 m
2
, and 108 (2.8%)
subjects had an eGFR less than 30 mL/min/1.73 m
2
. Differences in safety or effectiveness were
not observed in the subgroup analyses.
No clinically relevant difference in the pharmacokinetics of TRESIBA
®
was identified in a study
comparing healthy subjects and subjects with renal impairment including subjects with end
stage renal disease
[see Clinical Pharmacology (12.3)]
. However, as with all insulin products,
glucose monitoring should be intensified and the TRESIBA
®
dosage adjusted on an individual
basis in patients with renal impairment.
8.7 Hepatic Impairment
No difference in the pharmacokinetics of TRESIBA
®
was identified in a study comparing healthy
subjects and subjects with hepatic impairment (mild, moderate, and severe hepatic impairment)
[see Clinical Pharmacology (12.3)]
. However, as with all insulin products, glucose monitoring
should be intensified and the TRESIBA
®
dosage adjusted on an individual basis in patients with
hepatic impairment.
10 OVERDOSAGE
An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and
sometimes prolonged and life-threatening hypoglycemia and hypokalemia
[see Warnings and
Precautions (5.3, 5.6)]
. Mild episodes of hypoglycemia usually can be treated with oral glucose.
Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes of
hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/
subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery
from hypoglycemia, continued observation and additional carbohydrate intake may be necessary
to avoid reoccurrence of hypoglycemia. Hypokalemia must be corrected appropriately.
11 DESCRIPTION
TRESIBA
®
(insulin degludec injection) is a long-acting basal human insulin analog for
subcutaneous injection. Insulin degludec is produced by a process that includes expression of
recombinant DNA in
Saccharomyces cerevisiae
followed by chemical modification.
Insulin degludec differs from human insulin in that the amino acid threonine in position B30
has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been
attached (chemical name: LysB29(N
ε
-hexadecandioyl-
γ
-Glu) des(B30) human insulin). Insulin
degludec has a molecular formula of C
274
H
411
N
65
O
81
S
6
and a molecular weight of 6103.97. It has
the following structure:
