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TRESIBA ® (insulin degludec injection) 3
6 ADVERSE REACTIONS
The following adverse reactions are also discussed elsewhere:
• Hypoglycemia
[see Warnings and Precautions (5.3)]
• Medication errors [see Warnings and Precautions (5.4)]
• Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)]
• Hypokalemia [see Warnings and Precautions (5.6)]
6.1 Clinical Trial Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates
observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials
of another drug and may not reflect the rates observed in practice.
The safety of TRESIBA
® in subjects with type 1 diabetes or type 2 diabetes was evaluated in
nine trials of 6-12 month duration in adults and in one trial of 12-month duration in pediatric
patients 1 year of age and older with type 1 diabetes. The cardiovascular safety of TRESIBA ® was
evaluated in one double-blinded, event-driven trial of 2-year median duration in patients with
type 2 diabetes at high risk of cardiovascular events [see Clinical Studies (14)] .
The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to TRESIBA
®
with a
mean exposure duration to TRESIBA ® of 34 weeks in three open-label trials. The mean age was
43 years and 1% were older than 75 years. Fifty-seven percent were male, 81% were White, 2%
were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 26
kg/m 2 . The mean duration of diabetes was 18 years and the mean HbA
1c
at baseline was 7.8%.
A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline
was reported in 11%, 16%, 7% and 0.5% respectively. The mean eGFR at baseline was 87 mL/
min/1.73 m
2
and 7% of the patients had an eGFR less than 60 mL/min/1.73 m
2
.
The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to TRESIBA ® with a
mean exposure duration to TRESIBA
®
of 36 weeks in six open-label trials. The mean age was
58 years and 3% were older than 75 years. Fifty-eight percent were male, 71% were White, 7%
were Black or African American and 13% were Hispanic. The mean BMI was 30 kg/m
2
. The
mean duration of diabetes was 11 years and the mean HbA
1c
at baseline was 8.3%. A history of
neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported
for 14%, 10%, 6% and 0.6% of participants respectively. At baseline, the mean eGFR was 83
mL/min/1.73 m 2 and 9% had an eGFR less than 60 mL/min/1.73 m 2 .
Common adverse reactions (excluding hypoglycemia) occurring in TRESIBA ® treated subjects
during clinical trials in adult patients with type 1 diabetes mellitus and adults with type 2 diabetes
mellitus are listed in Table 1 and Table 2, respectively. Common adverse reactions were defined
as reactions occurring in ≥ 5% of the population studied. Hypoglycemia is not shown in these
tables but discussed in a dedicated subsection below.
174 pediatric patients 1 year of age and older with type 1 diabetes were exposed to TRESIBA
®
with a mean exposure to TRESIBA ® of 48 weeks. The mean age was 10 years: 25% were ages
1-5 years, 40% were ages 6-11 years, and 35% were ages 12-17 years. 55.2% were male, 78.2%
were White, 2.9% were Black or African American and 4% were Hispanic. The mean body mass
index (BMI) was 18.7 kg/m 2 . The mean duration of diabetes was 3.9 years and the mean HbA
1c
at
baseline was 8.2%. Common adverse reactions in TRESIBA
®
treated pediatric patients with type
1 diabetes mellitus were similar to the adverse reactions listed in Table 1.
Table 1: Adverse Reactions Occurring in ≥ 5% of TRESIBA
®
-Treated Adult Patients
with Type 1 Diabetes Mellitus
Adverse Reaction
TRESIBA
®
(n=1102)
Nasopharyngitis 23.9 %
Upper respiratory tract infection 11.9 %
Headache 11.8 %
Sinusitis 5.1 %
Gastroenteritis 5.1 %
Table 2: Adverse Reactions Occurring in ≥ 5% of TRESIBA
®
-Treated Adult Patients
with Type 2 Diabetes Mellitus
Adverse Reaction
TRESIBA ®
(n=2713)
Nasopharyngitis 12.9 %
Headache 8.8 %
Upper respiratory tract infection 8.4 %
Diarrhea 6.3 %
Hypoglycemia
Hypoglycemia is the most commonly observed adverse reaction in patients using insulin,
including TRESIBA
®
[see Warnings and Precautions (5.3)] . The rates of reported hypoglycemia
depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose
control, background therapies, and other intrinsic and extrinsic patient factors. For these
reasons, comparing rates of hypoglycemia in clinical trials for TRESIBA ® with the incidence
of hypoglycemia for other products may be misleading and also, may not be representative of
hypoglycemia rates that will occur in clinical practice.
In the open-label adult clinical trials of patients with type 1 and type 2 diabetes, and in the
open-label pediatric clinical trial of patients with type 1 diabetes, percentages of adult and
pediatric patients with type 1 diabetes randomized to TRESIBA
®
who experienced at least one
episode of hypoglycemia in clinical trials [see Clinical Studies (14)] and adults with type 2
diabetes are shown in Tables 3 and 4, respectively.
Severe hypoglycemia in the open-label trials with adult patients was defined as an episode
requiring assistance of another person to actively administer carbohydrate, glucagon, or other
resuscitative actions. Severe hypoglycemia in the pediatric trial was defined as an altered mental
status where the child could not assist in his own care, was semiconscious or unconscious, or
in a coma ± convulsions and may require parenteral therapy (glucagon or intravenous glucose).
A Novo Nordisk hypoglycemia episode was defined as a severe hypoglycemia episode or an
episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56
mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence
of hypoglycemic symptoms).
Table 3: Percent (%) of Type 1 Diabetes Patients Experiencing at Least One
Episode of Severe Hypoglycemia or Novo Nordisk Hypoglycemia
§
on TRESIBA
®
in
Open-Label Adult and Pediatric Clinical Trials
Study A
Adults
+ insulin
aspart
52 weeks
Study B
Adults
+ insulin
aspart
26 weeks
Study C
Adults
+ insulin aspart
26 weeks
Study J
Pediatrics
+ insulin
aspart
52 weeks
TRESIBA
®
(N=472)
TRESIBA
®
(N=301)
TRESIBA ®
at the same
time each day
(N=165)
TRESIBA ® at
alternating
times
(N=164)
TRESIBA
®
(N=174)
Severe hypoglycemia*
Percent of patients 12.3% 10.6% 12.7% 10.4% 17.8%
Novo Nordisk hypoglycemia
§
Percent of patients 95.6% 93.0% 99.4% 93.9% 98.3%
*
Severe hypoglycemia in pediatric patients: an episode with altered mental status, where the child could
not assist in his own care, was semiconscious or unconscious, or in a coma ± convulsions and may require
parenteral therapy (glucagon or intravenous glucose).
§ Novo Nordisk hypoglycemia: a severe hypoglycemia episode or an episode where a laboratory or a self-
measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less than
50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms).
Table 4: Percent (%) of Patients with Type 2 Diabetes Experiencing at Least One
Episode of Severe Hypoglycemia or Novo Nordisk Hypoglycemia § on TRESIBA ® in
Open-Label Adult Clinical Trials
Study D
+ 1-2
OADs*
insulin
naïve
52 weeks
Study E
+ 1-2
OADs*
insulin
naïve
26 weeks
Study F
± 1-3
OADs*
insulin
naïve
26 weeks
Study G
T2DM ± 0-3 OADs*
26 weeks
Study H
T2DM ±
0-2
OADs* +
insulin
aspart
52 weeks
Study I
T2DM ±
1-2
OADs*
insulin
naïve
26 weeks
TRESIBA ®
(N=766)
TRESIBA ®
(N=228)
TRESIBA ®
(N=284)
TRESIBA ®
(N=226)
TRESIBA ®
(alternating
time)
(N=230)
TRESIBA ®
(N=753)
TRESIBA ®
(N=226)
Severe Hypoglycemia
Percent of
patients
0.3% 0 0 0.9% 0.4% 4.5% 0.4%
Novo Nordisk Hypoglycemia
§
Percent of
patients
46.5% 28.5% 50% 43.8% 50.9% 80.9% 42.5%
*OAD: oral antidiabetic agent,
§
Novo Nordisk hypoglycemia: a severe hypoglycemia episode or an episode
where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or where a whole
blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms).
Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions,
angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including
TRESIBA ® and may be life threatening [see Warnings and Precautions (5.5)] . Hypersensitivity
(manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and
urticaria were reported in 0.9% of patients treated with TRESIBA ® .
Lipodystrophy
Long-term use of insulin, including TRESIBA
®
, can cause lipodystrophy at the site of repeated
insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and
lipoatrophy (thinning of adipose tissue) and may affect insulin absorption [see Dosage and
Administration (2.1)] . In the clinical program, lipodystrophy, lipohypertrophy, or lipoatrophy was
reported in 0.3% of patients treated with TRESIBA
®
.
Injection Site Reactions
Patients taking TRESIBA
®
may experience injection site reactions, including injection site
hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and
injection site mass. In the clinical program, injection site reactions occurred in 3.8% of patients
treated with TRESIBA ® .
Weight Gain
Weight gain can occur with insulin therapy, including TRESIBA
®
, and has been attributed to the
anabolic effects of insulin. In the clinical program after 52 weeks of treatment, patients with type
1 diabetes treated with TRESIBA
®
gained an average of 1.8 kg and patients with type 2 diabetes
treated with TRESIBA ® gained an average of 3.0 kg.
Peripheral Edema
Insulin, including TRESIBA ® , may cause sodium retention and edema. In the clinical program,
peripheral edema occurred in 0.9% of patients with type 1 diabetes mellitus and 3.0% of patients
with type 2 diabetes mellitus treated with TRESIBA ® .