TRESIBA FlexTouch User manual

1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TRESIBA®
safely and effectively. See full prescribing information for TRESIBA®.
TRESIBA®(insulin degludec injection), for subcutaneous use
Initial U.S. Approval: 2015
——— RECENT MAJOR CHANGES ———
Dosage and Administration (2.1) 11/2018
Warnings and Precautions (5.1) 11/2018
——— INDICATIONS AND USAGE ———
TRESIBA®is a long-acting human insulin analog indicated to improve glycemic control in
patients 1 year of age and older with diabetes mellitus (1).
Limitations of Use:
• Not recommended for treating diabetic ketoacidosis.
——— DOSAGE AND ADMINISTRATION ———
• See Full Prescribing Information for important administration instructions (2.1).
• Rotate injection sites to reduce the risk of lipodystrophy (2.1).
• For pediatric patients requiring less than 5 units of TRESIBA®each day, use a TRESIBA®
U-100 vial (2.1).
• In adults, inject subcutaneously once daily at any time of day (2.2).
• In pediatric patients inject subcutaneously once daily at the same time every day (2.2).
• Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring
results and glycemic control goal (2.2).
• The recommended days between dose increases are 3 to 4 days (2.2).
• See Full Prescribing Information for recommended starting dose in insulin naïve patients and
patients already on insulin therapy (2.3, 2.4).
——— DOSAGE FORMS AND STRENGTHS ———
TRESIBA®injection is available in the following package sizes:
• 100 units/mL (U-100): 3 mL single-patient-use FlexTouch®(3).
• 200 units/mL (U-200): 3 mL single-patient-use FlexTouch®(3).
• 100 units/mL (U-100): 10 mL multiple-dose vial (3).
——— CONTRAINDICATIONS ———
• During episodes of hypoglycemia (4).
• Hypersensitivity to TRESIBA®or one of its excipients (4).
——— WARNINGS AND PRECAUTIONS ———
•Never share a TRESIBA®FlexTouch®pen between patients, even if the needle is changed (5.1).
• Hyper- or hypoglycemia with changes in insulin regimen: Carry out under close medical
supervision and increase frequency of blood glucose monitoring (5.2).
• Hypoglycemia: May be life-threatening. Increase monitoring with changes to: insulin dosage,
co-administered glucose lowering medications, meal pattern, physical activity; and in
patients with renal impairment or hepatic impairment or hypoglycemia unawareness (5.3,
5.4, 6.1).
• Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can
occur. Instruct patients to check insulin labels before injection. DO NOT transfer TRESIBA®
into a syringe for administration as overdosage and severe hypoglycemia can result (5.4).
• Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including
anaphylaxis, can occur. Discontinue TRESIBA®, monitor and treat if indicated (5.5).
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for
hypokalemia and treat if indicated (5.6).
•Fluid retention and heart failure with concomitant use of Thiazolidinediones (TZDs): Observe
for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart
failure occurs (5.7).
——— ADVERSE REACTIONS ———
Adverse reactions commonly associated with TRESIBA®are:
• hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash,
edema and weight gain (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at
1-800-727-6500 or FDA at 1−800−FDA−1088 or www.fda.gov/medwatch.
——— DRUG INTERACTIONS ———
• Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors,
angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine
oxidase inhibitors, pentoxifylline, pramlintide, propoxyphene, salicylates, somatostatin
analog (e.g., octreotide), and sulfonamide antibiotics (7).
• Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics,
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 (7).
• Drugs that may increase or decrease the blood glucose lowering effect: Alcohol, beta-
blockers, clonidine, lithium salts, and pentamidine (7).
• Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine,
guanethidine, and reserpine (7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient
labeling.
Revised: 11/2018
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
2.2 General Dosing Instructions
2.3 Starting Dose in Insulin Naïve Patients
2.4 Starting Dose in Patients Already on Insulin Therapy
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Never Share a TRESIBA®FlexTouch®Pen, Needle, or Syringe Between Patients
5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
5.3 Hypoglycemia
5.4 Hypoglycemia Due to Medication Errors
5.5 Hypersensitivity and Allergic Reactions
5.6 Hypokalemia
5.7 Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR
Gamma Agonist
6 ADVERSE REACTIONS
6.1 Clinical Trial Experience
6.2 Immunogenicity
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Renal Impairment
8.7 Hepatic Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Type 1 Diabetes – Adult
14.2 Type 1 Diabetes – Pediatric Patients 1 Year of Age and Older
14.3 Type 2 Diabetes – Adult
14.4 Safety Outcomes Trial
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 How Supplied
16.2 Recommended Storage
17 PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.

TRESIBA®(insulin degludec injection) 2
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
TRESIBA®is indicated to improve glycemic control in patients 1 year of age and older with
diabetes mellitus.
Limitations of Use
• Not recommended for the treatment of diabetic ketoacidosis.
2 DOSAGE AND ADMINISTRATION
2.1 Important Administration Instructions
• Always check insulin labels before administration [see Warnings and Precautions (5.4)].
• Inspect visually for particulate matter and discoloration. Only use TRESIBA®if the solution
appears clear and colorless.
• Inject TRESIBA®subcutaneously into the thigh, upper arm, or abdomen.
• Rotate injection sites within the same region from one injection to the next to reduce the risk
of lipodystrophy [see Adverse Reactions (6.1)].
• For pediatric patients requiring less than 5 units of TRESIBA®each day, use the
TRESIBA®U-100 vial.
• Use TRESIBA®with caution in patients with visual impairment that may rely on audible
clicks to dial their dose.
• DO NOT administer TRESIBA®intravenously or in an insulin infusion pump.
• DO NOT dilute or mix TRESIBA®with any other insulin products or solutions.
• DO NOT transfer TRESIBA®from the TRESIBA®pen into a syringe for administration [see
Warnings and Precautions (5.4)].
2.2 General Dosing Instructions
• TRESIBA®is available in 2 concentrations (U-100 and U-200):
oTRESIBA®U-100 concentration is available in 2 presentations, FlexTouch®pen and vial
•TRESIBA®U-100 single-patient-use FlexTouch®pen contains 300 units of
TRESIBA®U-100. It delivers doses in 1 unit increments and can deliver up to 80 units
in a single injection.
•TRESIBA®U-100 multiple-dose vial contains 1000 units of TRESIBA®U-100. Use vial
only with a U-100 insulin syringe.
oTRESIBA®U-200 concentration is only available in a FlexTouch®pen
•TRESIBA®U-200 single-patient-use FlexTouch®pen contains 600 units of
TRESIBA®U-200. It delivers doses in 2 unit increments and can deliver up to 160 units
in a single injection.
• DO NOT perform dose conversion when using the TRESIBA®U-100 or U-200 pens. The dose
window shows the number of insulin units to be delivered and no conversion is needed.
• In adults, inject TRESIBA®subcutaneously once-daily at any time of day.
• In pediatric patients inject TRESIBA®subcutaneously once-daily at the same time every day.
• Individualize and titrate the dose of TRESIBA®based on the patient’s metabolic needs, blood
glucose monitoring results, and glycemic control goal.
• The recommended days between dose increases are 3 to 4 days.
• Dose adjustments may be needed with changes in physical activity, changes in meal patterns
(i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or
during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings
and Precautions (5.3)].
• For adult patients, instruct patients who miss a dose of TRESIBA®to inject their daily dose
during waking hours upon discovering the missed dose. Instruct patients to ensure that at
least 8 hours have elapsed between consecutive TRESIBA®injections.
• For pediatric patients, instruct patients who miss a dose of TRESIBA®to contact their
healthcare provider for guidance and to monitor blood glucose levels more frequently until
the next scheduled TRESIBA®dose.
2.3 Starting Dose in Insulin Naïve Patients
Type 1 Diabetes Mellitus:
The recommended starting dose of TRESIBA®in insulin naïve patients with type 1 diabetes is
approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily
insulin dose should be administered as a short-acting insulin and divided between each daily
meal. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to
calculate the initial total daily insulin dose in insulin naïve patients with type 1 diabetes.
Type 2 Diabetes Mellitus:
The recommended starting dose of TRESIBA®in insulin naïve patients with type 2 diabetes
mellitus is 10 units once daily.
2.4 Starting Dose in Patients Already on Insulin Therapy
Adults with Type 1 or Type 2 Diabetes Mellitus:
Start TRESIBA®at the same unit dose as the total daily long or intermediate-acting insulin unit
dose.
Pediatric Patients 1 Year of Age and Older with Type 1 or Type 2 Diabetes Mellitus:
Start TRESIBA®at 80% of the total daily long or intermediate-acting insulin unit dose to minimize
the risk of hypoglycemia [see Warnings and Precautions (5.2)].
3 DOSAGE FORMS AND STRENGTHS
Injection: TRESIBA®is available as a clear and colorless solution:
• 100 units/mL (U-100): 3 mL single-patient-use FlexTouch®disposable prefilled pen
• 100 units/mL (U-100): 10 mL multiple-dose vial
• 200 units/mL (U-200): 3 mL single-patient-use FlexTouch®disposable prefilled pen
4 CONTRAINDICATIONS
TRESIBA®is contraindicated:
• During episodes of hypoglycemia [see Warnings and Precautions (5.3)].
• In patients with hypersensitivity to TRESIBA®or one of its excipients [see Warnings and
Precautions (5.5)].
5 WARNINGS AND PRECAUTIONS
5.1 Never Share a TRESIBA®FlexTouch®Pen, Needle, or Syringe Between
Patients
TRESIBA®FlexTouch®disposable prefilled pens should never be shared between patients, even
if the needle is changed. Patients using TRESIBA®vials should never share needles or syringes
with another person. Sharing poses a risk for transmission of blood-borne pathogens.
5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen
Changes in insulin, manufacturer, type, or method of administration may affect glycemic control
and predispose to hypoglycemia or hyperglycemia. These changes should be made cautiously
and only under medical supervision and the frequency of blood glucose monitoring should be
increased. For patients with type 2 diabetes, adjustments in concomitant anti-diabetic treatment
may be needed. When converting from other insulin therapies to TRESIBA®follow dosing
recommendations [see Dosage and Administration (2.4)].
5.3 Hypoglycemia
Hypoglycemia is the most common adverse reaction of insulin, including TRESIBA®[see
Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening or
cause death. Hypoglycemia can impair concentration ability and reaction time; this may place
an individual and others at risk in situations where these abilities are important (e.g., driving or
operating other machinery). TRESIBA®, or any insulin, should not be used during episodes of
hypoglycemia [see Contraindications (4)].
Hypoglycemia can happen suddenly and symptoms may differ in each individual and change
over time in the same individual. Symptomatic awareness of hypoglycemia may be less
pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in
patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see
Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.
Risk Factors for Hypoglycemia
The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of
hypoglycemia after an injection is related to the duration of action of the insulin [see Clinical
Pharmacology (12.2)] and, in general, is highest when the glucose lowering effect of the insulin is
maximal. As with all insulin preparations, the glucose lowering effect time course of TRESIBA®
may vary among different individuals or at different times in the same individual and depends
on many conditions, including the area of injection as well as the injection site blood supply and
temperature.
Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g.,
macronutrient content or timing of meals), changes in level of physical activity, or changes to
co-administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment
may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].
Risk Mitigation Strategies for Hypoglycemia
Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-
monitoring of blood glucose plays an essential role in the prevention and management of
hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced
symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is
recommended.
5.4 Hypoglycemia Due to Medication Errors
Accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting
insulins, have been reported. To avoid medication errors between TRESIBA®and other insulins,
instruct patients to always check the insulin label before each injection.
To avoid dosing errors and potential overdose, never use a syringe to remove TRESIBA®from the
TRESIBA®FlexTouch®disposable insulin prefilled pen [see Dosage and Administration (2.1) and
Warnings and Precautions (5.3)].
5.5 Hypersensitivity and Allergic Reactions
Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin
products, including TRESIBA®. If hypersensitivity reactions occur, discontinue TRESIBA®; treat
per standard of care and monitor until symptoms and signs resolve. TRESIBA®is contraindicated
in patients who have had hypersensitivity reactions to insulin degludec or one of the excipients
[see Contraindications (4)].
5.6 Hypokalemia
All insulin products, including TRESIBA®, cause a shift in potassium from the extracellular
to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause
respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at
risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients
taking medications sensitive to serum potassium concentrations).
5.7 Fluid Retention and Congestive Heart Failure with Concomitant Use of a
PPAR Gamma Agonist
Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-
gamma agonists can cause dose related fluid retention, particularly when used in combination
with insulin. Fluid retention may lead to or exacerbate congestive heart failure. Patients treated
with insulin, including TRESIBA®and a PPAR-gamma agonist should be observed for signs
and symptoms of congestive heart failure. If congestive heart failure develops, it should be
managed according to current standards of care and discontinuation or dose reduction of the
PPAR-gamma agonist must be considered.

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/m2. The mean duration of diabetes was 18 years and the mean HbA1c 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 m2and 7% of the patients had an eGFR less than 60 mL/min/1.73 m2.
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/m2. The
mean duration of diabetes was 11 years and the mean HbA1c 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 m2and 9% had an eGFR less than 60 mL/min/1.73 m2.
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/m2. The mean duration of diabetes was 3.9 years and the mean HbA1c 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®.

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 HbA1c >7 and has been reported to be as high as 20-25% in women with
an HbA1c >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 m2and 1 (0.1%) had an
eGFR less than 30 mL/min/1.73 m2. 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 m2and no subjects had an eGFR
less than 30 mL/min/1.73 m2.
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 m2, and 108 (2.8%)
subjects had an eGFR less than 30 mL/min/1.73 m2. 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(Nε-hexadecandioyl-γ-Glu) des(B30) human insulin). Insulin
degludec has a molecular formula of C274H411N65O81S6and a molecular weight of 6103.97. It has
the following structure:

TRESIBA®(insulin degludec injection) 5
Figure 1: Structural Formula of TRESIBA®
GlyIle ValGlu GlnCys CysThr SerIle CysSer LeuTyr GlnLeu GluAsn TyrCys Asn
PheVal AsnGln HisLeu CysGly SerHis LeuVal GluAla LeuTyr LeuVal CysGly GluArg GlyPhe PheTyr ThrPro
H
OH
H
H
NB29
O
OH
HN
O
NH
(CH2)14
O
HO
O
HO
O
A1 A10A20
B1 B10B20
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
0612 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 (GIRmax) 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 AUCGIR,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 (tmax). 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 (Clcr) 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 (AUCIDeg,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/FIDeg,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