Levemir PI

——— DOSAGE FORMS AND STRENGTHS ———

Injection: 100 units/mL (U-100) of insulin detemir available as:

• 3 mL single-patient-use FlexPen

preﬁlled pen (3)

• 10 mL multiple-dose vial (3)

——— CONTRAINDICATIONS ———

• During episodes of hypoglycemia (4)

• Hypersensitivity to insulin detemir or any of the excipients in

LEVEMIR

(4)

——— WARNINGS AND PRECAUTIONS ———

• Never Share a LEVEMIR

FlexPen

, insulin syringe, or needle

between patients, even if the needle is changed (5.1).

• Hyperglycemia or hypoglycemia with changes in insulin

regimen: Make changes to a patient’s insulin regimen

(e.g.,insulin strength, manufacturer, type, injection site or

method of administration) under close medical supervision with

increased frequency of blood glucose monitoring (5.2).

• Hypoglycemia: May be life-threatening. Increase frequency

of glucose monitoring with changes to: insulin dosage,

concomitant drugs, meal pattern, physical activity; and in

patients with renal impairment or hepatic impairment or hypo-

glycemia unawareness (5.3).

• Hypoglycemia due to medication errors: Accidental mix-ups

between insulin products can occur. Instruct patients to check

insulin labels before injection (5.4).

• Hypersensitivity reactions: Severe, life-threatening, generalized

allergy, including anaphylaxis, can occur. Discontinue

LEVEMIR

, 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 thia-

zolidinediones (TZDs): Observe for signs and symptoms of heart

failure; consider dosage reduction or discontinuation if heart

failure occurs (5.7).

——— ADVERSE REACTIONS ———

Adverse reactions associated with LEVEMIR

include hypogly-

cemia, allergic reactions, injection site reactions, lipodystrophy,

rash and pruritus (6).

To report SUSPECTED ADVERSE REACTIONS, contact

Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-

FDA-1088 or www.fda.gov/medwatch.

——— DRUG INTERACTIONS ———

• Drugs that Affect Glucose Metabolism: Adjustment of insulin

dosage may be needed. (7)

• Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethi-

dine, and reserpine): Signs and symptoms of hypoglycemia may

be reduced or absent. (5.3, 7)

See 17 for PATIENT COUNSELING INFORMATION and

FDA-approved patient labeling.

Revised: 12/2022

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 Switching to LEVEMIR

from Other Insulin Therapies

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Never Share a LEVEMIR

FlexPen

, Needle, or

Insulin 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 Reactions

5.6 Hypokalemia

5.7 Fluid Retention and Heart Failure with Concomitant

Use of PPAR-gamma Agonists

6 ADVERSE REACTIONS

6.1 Clinical Trial Experience

6.2 Postmarketing Experience

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 Clinical Studies in Adult Patients with Type 1 Diabetes

14.2 Clinical Studies in Pediatric Patients with Type 1

Diabetes

14.3 Clinical Studies in Adult Patients with Type 2 Diabetes

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

* Sections or subsections omitted from the full prescribing

information are not listed.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information

needed to use LEVEMIR

safely and effectively.

See full prescribing information for LEVEMIR

LEVEMIR

(insulin detemir) injection, forsubcuta-

neoususe

Initial U.S. Approval: 2005

——— INDICATIONS AND USAGE ———

LEVEMIR

is a long-acting human insulin analog indicated to

improve glycemic control in adult and pediatric patients with

diabetes mellitus (1).

Limitations of Use:

Not recommended for the treatment of diabetic ketoacidosis.

——— DOSAGE AND ADMINISTRATION ———

• See Full Prescribing Information for important administration

instructions (2.1).

• Inject subcutaneously into the thigh, upper arm, or abdomen

(2.1).

• Rotate injection sites to reduce risk of lipodystrophy and

localized cutaneous amyloidosis (2.1).

• Individualize and titrate the dose of LEVEMIR

based on the

patient’s metabolic needs, blood glucose monitoring results, and

glycemic control goal (2.2).

• Administer subcutaneously once daily or in divided doses twice

daily (2.2).

• See Full Prescribing Information for recommended starting dose

in insulin naïve patients and patients already on insulin therapy

(2.3, 2.4).

2LEVEMIR

(insulin detemir) injection

resolve. LEVEMIR

is contraindicated in patients who have had

hypersensitivity reactions to insulin detemir or any of the excipients.

5.6 Hypokalemia

All insulins, including LEVEMIR

, 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 Heart Failure with Concomitant

Use of PPAR-gamma Agonists

Thiazolidinediones (TZDs), which are peroxisome proliferator-

activated receptor (PPAR)-gamma agonists, can cause dose-related

ﬂuid retention, when used in combination with insulin. Fluid

retention may lead to or exacerbate heart failure. Patients treated with

insulin, including LEVEMIR

, and a PPAR-gamma agonist should

be observed for signs and symptoms of heart failure. If 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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.3)]

• Hypoglycemia Due to Medication errors [see Warnings and

Precautions (5.4)]

• Hypersensitivity 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 designs,

the adverse reaction rates reported in one clinical trial may not be

easily compared to those rates reported in another clinical trial, and

may not reﬂect the rates actually observed in clinical practice.

The frequencies of adverse reactions (excluding hypoglycemia)

reported during LEVEMIR

clinical trials in patients with type 1

diabetes mellitus and type 2 diabetes mellitus are listed in Tables 1-4

below. See Tables 5 and 6 for the hypoglycemia ﬁndings.

In two pooled trials, adults with type 1 diabetes were exposed to

individualized doses of LEVEMIR

(n=767) or NPH (n=388). The

mean duration of exposure to LEVEMIR

was 153 days, and the total

exposure to LEVEMIR

was 321 patient-years. The most common

adverse reactions are summarized in Table 1.

Table 1: Adverse Reactions Occurring in ≥5% of

LEVEMIR

-Treated Adult Patients with Type 1 Diabetes

Mellitus in Two Trials of 16 Weeks and 24 Weeks Duration

LEVEMIR

, %

(n=767)

Upper respiratory tract infection 26.1

Headache 22.6

Pharyngitis 9.5

Inﬂuenza-like illness 7.8

Abdominal Pain 6.0

Adults with type 1 diabetes were exposed to LEVEMIR

(n=161)

or insulin glargine (n=159). The mean duration of exposure to

LEVEMIR

was 176 days, and the total exposure to LEVEMIR

was 78 patient-years. The most common adverse reactions are

summarized in Table 2.

Table 2: Adverse Reactions Occurring in ≥5% of

LEVEMIR

-Treated Adult Patients with Type 1 Diabetes

Mellitus in a 26-week Trial

LEVEMIR

, %

(n=161)

Upper respiratory tract infection 26.7

Headache 14.3

Back pain 8.1

Inﬂuenza-like illness 6.2

Gastroenteritis 5.6

Bronchitis 5.0

In two pooled trials, adults with type 2 diabetes were exposed to

LEVEMIR

(n=432) or NPH (n=437). The mean duration of exposure

to LEVEMIR

was 157 days, and the total exposure to LEVEMIR

was 186 patient-years. The most common adverse reactions were

comparable to that observed in adult patients with type 1 diabetes

mellitus; see Table 1.

Pediatric patients with type 1 diabetes were exposed to individualized

doses of LEVEMIR

(n=232) or NPH (n=115). The mean duration

of exposure to LEVEMIR

was 180 days, and the total exposure

to LEVEMIR

was 114 patient-years. The most common adverse

4 CONTRAINDICATIONS

LEVEMIR

is contraindicated:

• During episodes of hypoglycemia [see Warnings and Precautions

(5.3)]

• In patients with hypersensitivity to insulin detemir or any of the

excipients in LEVEMIR

. Reactions have included anaphylaxis

[see Warnings and Precautions (5.5) and Adverse Reactions

(6.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Never Share a LEVEMIR

FlexPen

, Needle, or

Insulin Syringe between Patients

LEVEMIR

FlexPen

preﬁlled pens must never be shared between

patients, even if the needle is changed. Patients using LEVEMIR

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 an insulin regimen (e.g., insulin strength, manufac-

turer, type, injection site or method of administration) may affect

glycemic control and predispose to hypoglycemia [see Warnings

and Precautions (5.4)] or hyperglycemia. Repeated insulin injections

into areas of lipodystrophy or localized cutaneous amyloidosis have

been reported to result in hyperglycemia; and a sudden change in the

injection site (to an unaffected area) has been reported to result in

hypoglycemia [see Adverse Reactions (6)].

Make any changes to a patient’s insulin regimen under close medical

supervision with increased frequency of blood glucose monitoring.

Advise patients who have repeatedly injected into areas of lipodys-

trophy or localized cutaneous amyloidosis to change the injection

site to unaffected areas and closely monitor for hypoglycemia. For

patients with type 2 diabetes, dosage adjustments of concomitant

antidiabetic products may be needed [see Dosage and Administration

(2.4)].

5.3 Hypoglycemia

Hypoglycemia is the most common adverse reaction of insulin,

including LEVEMIR

[see Adverse Reactions (6.1)]. Severe hypo-

glycemia can cause seizures, may be life-threatening or cause death.

Hypoglycemia can impair concentration ability and reaction time;

this may place the patient and others at risk in situations where these

abilities are important (e.g., driving or operating other machinery).

LEVEMIR

, or any insulin, should not be used during episodes of

hypoglycemia [see Contraindications (4)].

Hypoglycemia can happen suddenly and symptoms may differ in

each patient and change over time in the same patient. Symptomatic

awareness of hypoglycemia may be less pronounced in patients

with longstanding diabetes, in patients with diabetic neuropathy,

using drugs that block the sympathetic nervous system (e.g., beta-

blockers) [see Drug Interactions (7)], or 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 insulins, the glucose lowering

effect time course of LEVEMIR

may vary among different patients

or at different times in the same patient 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

concomitant drugs [see Drug Interactions (7)]. When a GLP-1

receptor agonist is used in combination with LEVEMIR

, the

LEVEMIR

dose may need to be lowered or more conservatively

titrated to minimize the risk of hypoglycemia [see Adverse Reactions

(6.1)]. 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 insulin products have been reported.

To avoid medication errors between LEVEMIR

and other insulins,

instruct patients to always check the insulin label before each

injection.

5.5 Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis,

can occur with insulins, including LEVEMIR

[see Adverse Reactions

(6.1)]. If hypersensitivity reactions occur, discontinue LEVEMIR

;

treat per standard of care and monitor until symptoms and signs

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

LEVEMIR

is indicated to improve glycemic control in adult and

pediatric patients with diabetes mellitus.

Limitations of Use

LEVEMIR

is 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)].

• Visually inspect for particulate matter and discoloration. Only use

LEVEMIR

if the solution appears clear and colorless.

• Inject LEVEMIR

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 and localized

cutaneous amyloidosis. Do not inject into areas of lipodys-

trophy or localized cutaneous amyloidosis [see Warnings and

Precautions (5.2), Adverse Reactions (6)].

• During changes to a patient’s insulin regimen, increase the

frequency of blood glucose monitoring [see Warnings and

Precautions (5.2)].

• Do not dilute or mix LEVEMIR

with any other insulin or

solution.

• Do not administer LEVEMIR

intravenously or in an insulin

infusion pump.

• LEVEMIR

FlexPen

dials in 1-unit increments.

• Use the LEVEMIR

FlexPen

with caution in patients with visual

impairment who may rely on audible clicks to dial their dose.

2.2 General Dosing Instructions

• LEVEMIR

can be administered by subcutaneous injection once

or twice daily. Administer once daily doses with the evening meal

or at bedtime. For twice daily dosing, administer the evening

dose with the evening meal, at bedtime, or 12 hours after the

morning dose.

• Individualize and titrate the dose of LEVEMIR

based on the

patient’s metabolic needs, blood glucose monitoring results, and

glycemic control goal.

• 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)].

• In patients with type 1 diabetes, LEVEMIR

must be used in a

regimen with rapid-acting or short-acting insulin.

2.3 Starting Dose in Insulin Naïve Patients

Recommended Starting Dosage in Patients with Type 1 Diabetes

The recommended starting dose of LEVEMIR

in patients with

type 1 diabetes mellitus 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 short-acting pre-meal insulin. 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.

Recommended Starting Dosage in Patients with Type 2 Diabetes

The recommended starting dose of LEVEMIR

in patients with type

2 diabetes mellitus inadequately controlled on oral antidiabetic

medications or a GLP-1 receptor agonist is 10 units (or 0.1 units/

kg to 0.2 units/kg) given once daily in the evening or divided into a

twice daily regimen.

2.4 Switching to LEVEMIR

from Other Insulin

Therapies

Dosage adjustments are recommended to lower the risk of hypogly-

cemia when switching patients to LEVEMIR

from another insulin

therapy [see Warnings and Precautions (5.3)].

• If converting from insulin glargine to LEVEMIR

, the change can

be done on a unit-to-unit basis.

• If converting from NPH insulin, the change can be done on a

unit-to-unit basis. However, some patients with type 2 diabetes

mellitus may require more LEVEMIR

than NPH insulin, as

observed in one trial [see Clinical Studies (14)].

3 DOSAGE FORMS AND STRENGTHS

Injection: 100 units/mL (U-100), is a clear, colorless, solution

available as:

• 3 mL single-patient-use FlexPen

preﬁlled pen

• 10 mL multiple-dose vial

3LEVEMIR

(insulin detemir) injection

Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis,

generalized skin reactions, angioedema, bronchospasm,

hypotension, and shock have occurred with insulin, including

LEVEMIR

, and may be life-threatening.

Insulin Initiation and Intensiﬁcation of Glucose Control

Intensiﬁcation or rapid improvement in glucose control has been

associated with a transitory, reversible ophthalmologic refraction

disorder, worsening of diabetic retinopathy, and acute painful

peripheral neuropathy. However, long-term glycemic control

decreases the risk of diabetic retinopathy and neuropathy.

Lipodystrophy

Long-term use of insulin, including LEVEMIR

, can cause lipo-

dystrophy 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)].

Weight Gain

Weight gain can occur with insulin therapy, including LEVEMIR

, and

has been attributed to the anabolic effects of insulin and the decrease

in glucosuria [see Clinical Studies (14)]. In the clinical program, the

mean change in body weight from baseline in adult patients with type

1 diabetes (Study A, B, and C) treated with LEVEMIR

ranged from

-0.3 kg to 0.5 kg. The mean change in body weight from baseline in

adult patients with type 2 diabetes (Study E, F, and H) treated with

LEVEMIR

ranged from 0.5 kg to 1.2 kg.

Peripheral Edema

Insulin, including LEVEMIR

, may cause sodium retention and

edema, particularly if previously poor metabolic control is improved

by intensiﬁed insulin therapy.

Injection Site Reactions

Patients taking LEVEMIR

may experience injection site reactions,

including localized erythema, pain, pruritus, urticaria, edema, and

inﬂammation. In clinical studies in adults, three patients treated with

LEVEMIR

reported injection site pain (0.25%).

Immunogenicity

All insulin products can elicit the formation of insulin antibodies.

These insulin antibodies may increase or decrease the efﬁcacy of

insulin and may require adjustment of the insulin dose. In clinical

trials of LEVEMIR

, antibody development has been observed with

no apparent impact on glycemic control.

6.2 Postmarketing Experience

The following adverse reactions have been identiﬁed during post

approval use of LEVEMIR

. Because these reactions are reported

voluntarily from a population of uncertain size, it is not always

possible to reliably estimate their frequency or establish a causal

relationship to drug exposure.

Medication errors have been reported in which rapid-acting or short-

acting insulins and other insulins, have been accidentally adminis-

tered instead of LEVEMIR

Localized cutaneous amyloidosis at the injection site has occurred.

Hyperglycemia has been reported with repeated insulin injections

into areas of localized cutaneous amyloidosis; hypoglycemia has

been reported with a sudden change to an unaffected injection site.

7 DRUG INTERACTIONS

Table 6 includes clinically signiﬁcant drug interactions with

LEVEMIR

Table 4: Hypoglycemia in Patients with Type 1 Diabetes

Severe Hypoglycemia Non-Severe Hypoglycemia

Percent of patients with at

least 1 event (n/total N)

Event/patient/year

Percent of patients

(n/total N)

Event/patient/year

Study A

Type 1 Diabetes

Adults

16 weeks

In combination with

insulinaspart

Twice-Daily

LEVEMIR

8.7

(24/276)

0.52

88.0

(243/276)

26.4

Study B

Type 1 Diabetes

Adults

26weeks

In combination with

insulinaspart

Twice-Daily

LEVEMIR

5.0

(8/161)

0.13

82.0

(132/161)

20.2

Study C

Type 1 Diabetes

Adults

24 weeks

In combination with

regularinsulin

Once-Daily

LEVEMIR

7.5

(37/491)

0.35

88.4

(434/491)

31.1

Study D

Type 1 Diabetes

Pediatrics

26weeks

In combination with

insulinaspart

Once- or Twice

Daily LEVEMIR

15.9

(37/232)

0.91

93.1

(216/232)

31.6

Study I

Type 1 Diabetes

Pediatrics

52 weeks

In combination with

insulin aspart

Once- or Twice

Daily LEVEMIR

1.7

(3/177)

0.02

94.9

(168/177)

56.1

Table 5: Hypoglycemia in Patients with Type 2 Diabetes

Study E

Type 2 Diabetes

Adults

24 weeks

In combination with

oralagents

Study F

Type 2 Diabetes

Adults

22 weeks

In combination with

insulin aspart

Study H

Type 2 Diabetes

Adults

26 weeks

in combination with

LiraglutideandMetformin

Twice-Daily

LEVEMIR

Once- or Twice Daily

LEVEMIR

Once Daily LEVEMIR

Liraglutide + Metformin

Severe

hypoglycemia

Percent of patients with at

least 1 event (n/total N)

0.4

(1/237)

1.5

(3/195)

Event/patient/year 0.01 0.04 0

Non-severe

hypoglycemia

Percent of patients

(n/total N)

40.5

(96/237)

32.3

(63/195)

9.2

(15/163)

Event/patient/year 3.5 1.6 0.29

reactions are summarized in Table 3.

Table 3: Adverse Reactions Occurring in ≥5% of

LEVEMIR

-Treated Pediatric Patients with Type 1

Diabetes Mellitus in a 26-week Trial

LEVEMIR

, %

(n=232)

Upper respiratory tract infection 35.8

Headache 31.0

Pharyngitis 17.2

Gastroenteritis 16.8

Inﬂuenza-like illness 13.8

Abdominal pain 13.4

Pyrexia 10.3

Cough 8.2

Viral infection 7.3

Nausea 6.5

Rhinitis 6.5

Vomiting 6.5

Hypoglycemia

Hypoglycemia was the most commonly observed adverse reaction

in patients treated with LEVEMIR

. The rates of reported hypogly-

cemia 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 LEVEMIR

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.

Table 4 (type 1 diabetes) and Table 5 (type 2 diabetes) summarize the

incidence of severe and non-severe hypoglycemia in the LEVEMIR

clinical trials.

For the adult trials and one of the pediatric trials (Study D), severe

hypoglycemia was deﬁned as an event with symptoms consistent

with hypoglycemia requiring assistance of another person and

associated with either a plasma glucose value below 56 mg/dL

(blood glucose below 50 mg/dL) or prompt recovery after oral

carbohydrate, intravenous glucose or glucagon administration. For

the other pediatric trial (Study I), severe hypoglycemia was deﬁned

as an event with semi-consciousness, unconsciousness, coma and/

or convulsions in a patient who could not assist in the treatment and

who may have required glucagon or intravenous glucose.

For the adult trials and pediatric trial (Study D), non-severe hypo-

glycemia was deﬁned as an asymptomatic or symptomatic plasma

glucose <56 mg/dL (or equivalently blood glucose <50 mg/dL as

used in Study A and C) that was self-treated by the patient. For

pediatric Study I, non-severe hypoglycemia included asymptom-

atic events with plasma glucose <65 mg/dL as well as symptomatic

events that the patient could self-treat or treat by taking oral therapy

provided by the caregiver.

4LEVEMIR

(insulin detemir) injection

can be treated with oral glucose. Lowering the insulin dosage, and

adjustments in meal patterns, or exercise may be needed. More

severe episodes with coma, seizure, or neurologic impairment may

be treated with a glucagon product for emergency use or concen-

trated intravenous glucose. After apparent clinical recovery from

hypoglycemia, continued observation and additional carbohydrate

intake may be necessary to avoid recurrence of hypoglycemia.

Hypokalemia must be corrected appropriately.

11 DESCRIPTION

Insulin detemir is a long-acting recombinant human insulin analog

produced by a process that includes expression of recombinant DNA

in Saccharomyces cerevisiae followed by chemical modiﬁcation.

Insulin detemir differs from human insulin in that the amino acid

threonine in position B30 has been omitted, and a C14 fatty acid

chain has been attached to the amino acid B29. Insulin detemir has a

molecular formula of C

267

402

and a molecular weight of

5.917 kDa. It has the following structure:

Figure 1: Structural Formula of Insulin Detemir

LEVEMIR

(insulin detemir) injection is a clear, colorless, aqueous,

neutral sterile solution for subcutaneous use. Each milliliter of

LEVEMIR

contains 100 units insulin detemir, dibasic sodium

phosphate (0.71 mg), glycerin (16 mg), metacresol (2.06 mg),

phenol (1.8 mg), sodium chloride (1.17 mg), zinc (65.4 mcg), and

Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide

may be added to adjust pH. LEVEMIR

has a pH of approximately

7.4.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The primary activity of insulin, including LEVEMIR

, is regulation of

glucose metabolism. Insulins 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.

12.2 Pharmacodynamics

Insulin detemir is a soluble, long-acting basal human insulin analog

with up to a 24-hour duration of action. The pharmacodynamic

proﬁle of LEVEMIR

is relatively constant with no pronounced peak.

The duration of action of LEVEMIR

is mediated by slowed systemic

absorption of insulin detemir molecules from the injection site due to

self-association of the drug molecules. In addition, the distribution

of insulin detemir to peripheral target tissues is slowed because of

binding to albumin.

Figure 2 shows results from a study in patients with type 1 diabetes

conducted for a maximum of 24 hours after the subcutaneous

injection of LEVEMIR

. The mean time between injection and the

end of pharmacological effect for insulin detemir ranged from 7.6

hours to >24 hours (24 hours was the end of the observation period).

Figure 2: Glucose Lowering Effect in Patients with Type 1

Diabetes in a 24-hour Glucose Clamp Study

8121620

6.0

4.0

2.0

0.0

Pharmacodynamic Parameters for LEVEMIR

AUC

GIR

(mg/kg)

GIR

max

(mg/kg/min)

LEVEMIR

0.2 U/kg 0.4 U/kg

419 1184

1.1 1.7

Glucose Infusion Rate (mg/kg/min)

Time Since Insulin Injection (hours)

LEVEMIR

0.2 Units/kg LEVEMIR

0.4 Units/kg

AUC

GIR

: Area Under Curve Glucose Infusion Rate

GIR

max

: Maximum Glucose Infusion Rate

For doses in the interval of 0.2 to 0.4 units/kg, insulin detemir

exerts more than 50% of its maximum effect from 3 to 4 hours up to

approximately 14 hours after dose administration.

Figure 3 shows glucose infusion rate results from a 16-hour glucose

clamp study in patients with type 2 diabetes. The clamp study was

terminated at 16 hours according to protocol.

preprandial insulin aspart. Approximately half of the study partici-

pants in each arm were randomized as pregnant and were exposed

to NPH or to other insulins prior to conception and in the ﬁrst 8

weeks of gestation. The rates of preeclampsia observed in the study

were within expected rates for pregnancy complicated by diabetes.

No differences in pregnancy outcomes or the health of the fetus

and newborn were seen between the two groups. In this study, the

proportion of subjects with severe hypoglycemia and non-severe

hypoglycemia was similar between the two treatment arms; for the

deﬁnitions of severe hypoglycemia and non-severe hypoglycemia

[see Adverse Reactions (6.1)].

In about a quarter of infants, LEVEMIR

was detected in the infant

cord blood at levels above the lower level of quantiﬁcation (<25

pmol/L).

Animal Data

In a fertility and embryonic development study, insulin detemir

was administered to female rats before mating, during mating, and

throughout pregnancy at doses up to 300 nmol/kg/day (3 times a

human dose of 0.5 units/kg/day, based on plasma area under the

curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day produced

numbers of litters with visceral anomalies. Doses up to 900 nmol/

kg/day (approximately 135 times a human dose of 0.5 units/kg/day

based on AUC ratio) were given to rabbits during organogenesis.

Drug and dose related increases in the incidence of fetuses with

gallbladder abnormalities such as small, bilobed, bifurcated, and

missing gallbladders were observed at a dose of 900 nmol/kg/day.

The rat and rabbit embryo-fetal development studies that included

concurrent human insulin control groups indicated that insulin

detemir and human insulin had similar effects regarding embryo-

toxicity and teratogenicity suggesting that the effects seen were the

result of hypoglycemia resulting from insulin exposure in normal

animals.

8.2 Lactation

Risk Summary

Available data from published literature demonstrate that exogenous

human insulin products, including biosynthetic insulins such

as insulin detemir, are transferred into human milk. There are no

published reports of adverse reactions, including hypoglycemia, in

breastfed infants exposed to exogenous human insulin products,

including insulin detemir, in breastmilk. There are no data on the

effects of exogenous human insulin products, including insulin

detemir, on milk production. The developmental and health beneﬁts

of breastfeeding should be considered along with the mother’s

clinical need for LEVEMIR

and any potential adverse effects on the

breastfed infant from LEVEMIR

or from the underlying maternal

condition.

8.4 Pediatric Use

The safety and effectiveness of LEVEMIR

to improve glycemic

control in pediatric patients with diabetes mellitus have been

established. The use of LEVEMIR

for this indication is supported

by evidence from adequate and well-controlled trials (Studies D and

I) in 694 pediatric patients aged 2 to 17 years with type 1 diabetes

mellitus [see Clinical Studies (14.2)] and from other studies in

pediatric patients and adults with diabetes mellitus [see Clinical

Pharmacology (12.3), Clinical Studies (14.3)].

8.5 Geriatric Use

In clinical trials of LEVEMIR

, 64 of 1624 patients (4%) in the

type 1 diabetes trials and 309 of 1082 patients (29%) in the type 2

diabetes trials were 65 years or older. A total of 52 (7 type 1 and 45

type 2) patients (2%) were 75 years or older. No overall differences

in safety or effectiveness were observed between these patients

and younger patients, but small sample sizes limits conclusions.

Greater sensitivity of some older individuals cannot be ruled out.

In geriatric patients, the initial dosing, dosage increments, and

maintenance dosage should be conservative to avoid hypoglycemia.

Hypoglycemia may be difﬁcult to recognize in the geriatric patients.

8.6 Renal Impairment

No difference was observed in the pharmacokinetics of LEVEMIR

between non-diabetic patients with kidney impairment and healthy

volunteers. However, some studies with human insulin have shown

increased circulating insulin concentrations in patients with kidney

impairment. Careful glucose monitoring and dose adjustments of

LEVEMIR

, may be necessary in patients with kidney impairment

[see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Non-diabetic patients with severe hepatic impairment had lower

systemic exposures to insulin detemir compared to healthy

volunteers. However, some studies with human insulin have shown

increased circulating insulin concentrations in patients with liver

impairment. Careful glucose monitoring and dosage adjustments of

LEVEMIR

, may be necessary in patients with hepatic impairment

[see Clinical Pharmacology (12.3)].

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

Table 6: Clinically Signiﬁcant Drug Interactions with

LEVEMIR

Drugs That May Increase the Risk of Hypoglycemia

Drugs:

Antidiabetic agents, ACE inhibitors, angiotensin II

receptor blocking agents, disopyramide, ﬁbrates,

ﬂuoxetine, monoamine oxidase inhibitors, pentoxi-

fylline, pramlintide, salicylates, somatostatin analogs

(e.g., octreotide), and sulfonamide antibiotics,

GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2

inhibitors.

Intervention:

Dosage reductions and increased frequency

of glucose monitoring may be required when

LEVEMIR

is co-administered with these drugs.

Drugs That May Decrease the Blood Glucose Lowering

Effect of LEVEMIR

Drugs:

Atypical antipsychotics (e.g., olanzapine and

clozapine), corticosteroids, danazol, diuretics,

estrogens, glucagon, isoniazid, niacin, oral contra-

ceptives, phenothiazines, progestogens (e.g., in oral

contraceptives), protease inhibitors, somatropin,

sympathomimetic agents (e.g.,albuterol,

epinephrine, terbutaline), and thyroid hormones.

Intervention:

Dosage increases and increased frequency

of glucose monitoring may be required when

LEVEMIR

is co-administered with these drugs.

Drugs That May Increase or Decrease the Blood Glucose

Lowering Effect of LEVEMIR

Drugs:

Alcohol, beta-blockers, clonidine, and lithium salts.

Pentamidine may cause hypoglycemia, which may

sometimes be followed by hyperglycemia.

Intervention:

Dosage adjustment and increased frequency

of glucose monitoring may be required when

LEVEMIR

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 LEVEMIR

is co-administered with

these drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published studies and postmarketing case

reports with LEVEMIR

use in pregnant women have not identiﬁed

a drug-associated risk of major birth defects, miscarriage, or

adverse maternal or fetal outcomes. In a randomized, parallel-group,

open-label clinical trial that included 152 pregnant women with type

1 diabetes who were administered LEVEMIR

once or twice daily,

beginning in gestational weeks 8 to 12 or prior to conception, no

clear evidence of maternal or fetal risk associated with LEVEMIR

was observed (see Data). There are risks to the mother and fetus

associated with poorly controlled diabetes in pregnancy (see Clinical

Considerations).

Animal reproduction studies were conducted in non-diabetic

pregnant rats and rabbits with insulin detemir administration at 3

and 135 times the human dose of 0.5 units/kg/day, respectively,

throughout pregnancy. Overall, the effects of insulin detemir did not

generally differ from those observed with regular human insulin (see

Data).

In the U.S. general population, the estimated background risk of major

birth defects and miscarriage in clinically recognized pregnancies is

2 to 4% and 15 to 20%, respectively. The estimated background risk

of major birth defects is 6 to 10% in women with pre-gestational

diabetes with a peri-conceptional HbA

>7 and has been reported to

be as high as 20 to 25% in women with a peri-conceptional HbA

>10. The estimated background risk of miscarriage for the indicated

population is unknown.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypoglycemia and hyperglycemia occur more frequently during

pregnancy in patients with pre-gestational diabetes. Poorly controlled

diabetes in pregnancy increases the maternal risk for diabetic keto-

acidosis, preeclampsia, spontaneous abortions, preterm delivery,

and delivery complications. Poorly controlled diabetes increases the

fetal risk for major birth defects, stillbirth, and macrosomia-related

morbidity.

Data

Human Data

In an open-label clinical trial, pregnant females with type 1 diabetes

(n=310) were treated with LEVEMIR

(once or twice daily) or NPH

insulin (once, twice, or thrice daily); both groups also received

5LEVEMIR

(insulin detemir) injection

Figure 3: Glucose Lowering Effect in Patients with Type 2

Diabetes in a 16-hour Glucose Clamp Study

0246810 12 14

6.0

5.5

5.0

4.5

4.0

3.5

3.0

2.5

2.0

1.5

1.0

0.5

0.0

Pharmacodynamic Parameters for LEVEMIR

AUC

GIR

(mg/kg)

GIR

max

(mg/kg/min)

LEVEMIR

0.6 U/kg 1.2 U/kg

1359 2333

Glucose Infusion Rate (mg/kg/min)

Time since Insulin Injection (hours)

LEVEMIR

0.6 Units/kg LEVEMIR

1.2 Units/kg

AUC

GIR

: Area Under Curve Glucose Infusion Rate

GIR

max

: Maximum Glucose Infusion Rate

12.3 Pharmacokinetics

Absorption

After subcutaneous injection of LEVEMIR

in healthy subjects and

in patients with diabetes, insulin detemir serum concentrations had a

relatively constant concentration/time proﬁle over 24 hours with the

maximum serum concentration (C

max

) reached between 6-8 hours

post-dose. Insulin detemir was more slowly absorbed after subcu-

taneous administration to the thigh where AUC

0-5h

was 30-40%

lower and AUC

0-inf

was 10% lower than the corresponding AUCs

with subcutaneous injections to the deltoid and abdominal regions.

The absolute bioavailability of insulin detemir is approximately 60%.

Distribution

Insulin detemir has an apparent volume of distribution of

approximately 0.1 L/kg. More than 98% of insulin detemir in the

bloodstream is bound to albumin. The results of in vitro and in

vivo protein binding studies demonstrate that there is no clinically

relevant interaction between insulin detemir and fatty acids or other

protein-bound drugs.

Elimination

After subcutaneous administration in patients with type 1 diabetes,

insulin detemir has a terminal half-life of 5 to 7 hours depending

on dose.

Speciﬁc Populations

Pediatric Patients

The pharmacokinetic properties of LEVEMIR

were studied in

pediatric patients 6-12 years, 13-17 years, and adults with type 1

diabetes. In pediatric patients 6-12 years, the insulin detemir plasma

area under the curve (AUC) and C

max

were increased by 10% and

24%, respectively, as compared to adults. There was no difference in

pharmacokinetics between pediatric patients 13-17 years and adults.

Geriatrics

In a clinical trial studying differences in pharmacokinetics of a single

subcutaneous dose of LEVEMIR

in young (20 to 35 years) versus

elderly (≥68 years) healthy subjects, the insulin detemir AUC was up

to 35% higher among the elderly subjects due to reduced clearance

[see Use in Speciﬁc Populations (8.5)].

Gender

No clinically relevant differences in pharmacokinetic parameters of

LEVEMIR

are observed between males and females.

Race

In two clinical pharmacology studies conducted in healthy Japanese

and Caucasian subjects, there were no clinically relevant differences

seen in pharmacokinetic parameters. The pharmacokinetics and

pharmacodynamics of LEVEMIR

were studied in a clamp study

comparing patients with type 2 diabetes of Caucasian, African-

American, and Latino origin. Dose-response relationships for

LEVEMIR

were comparable in these three populations.

Renal impairment

A single subcutaneous dose of 0.2 units/kg of LEVEMIR

was

administered to healthy subjects and those with varying degrees of

renal impairment (mild, moderate, severe, and hemodialysis-depen-

dent). In this study, there were no differences in the pharmacoki-

netics of LEVEMIR

between healthy subjects and those with renal

impairment [see Use in Speciﬁc Populations (8.6)].

Hepatic impairment

A single subcutaneous dose of 0.2 units/kg of LEVEMIR

was

administered to healthy subjects and those with varying degrees

of hepatic impairment (mild, moderate and severe). LEVEMIR

exposure as estimated by AUC decreased with increasing degrees

of hepatic impairment with a corresponding increase in apparent

clearance [see Use in Speciﬁc Populations (8.7)].

Smoking

The effect of smoking on the pharmacokinetics and pharmacody-

namics of LEVEMIR

has not been studied.

Liraglutide

No pharmacokinetic interaction was observed between liraglutide

and LEVEMIR

when separate subcutaneous injections of LEVEMIR

0.5 units/kg (single-dose) and liraglutide 1.8 mg (steady state) were

administered in patients with type 2 diabetes.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of

Fertility

Standard 2-year carcinogenicity studies in animals have not been

performed. Insulin detemir tested negative for genotoxic potential

in the in vitro reverse mutation study in bacteria, human peripheral

blood lymphocyte chromosome aberration test, and the in vivo

mouse micronucleus test.

In a fertility and embryonic development study, insulin detemirwas

administered to female rats before mating, during mating, and

throughout pregnancy at doses up to 300 nmol/kg/day (3 times a

human dose of 0.5 units/kg/day, based on plasma AUC ratio). There

were no effects on fertility in the rat.

14 CLINICAL STUDIES

The efﬁcacy and safety of LEVEMIR

given once-daily at bedtime

or twice-daily (before breakfast and at bedtime, before breakfast

and with the evening meal, or at 12-hour intervals) was compared

to that of once-daily or twice-daily NPH insulin in open-label,

randomized, parallel trials of 1155 adults with type 1 diabetes

mellitus, 347 pediatric patients with type 1 diabetes mellitus, and

869 adults with type 2 diabetes mellitus. The efﬁcacy and safety of

LEVEMIR

given twice-daily was compared to once-daily insulin

glargine in an open-label, randomized, parallel trial of 320 patients

with type 1 diabetes. The evening LEVEMIR

dose was titrated in all

trials according to pre-deﬁned targets for fasting blood glucose. The

pre-dinner blood glucose was used to titrate the morning LEVEMIR

dose in those trials that also administered LEVEMIR

in the morning.

In general, the reduction in HbA

with LEVEMIR

was similar to that

with NPH insulin or insulin glargine.

14.1 Clinical Studies in Adult Patients with Type 1

Diabetes

In a 16-week open-label clinical trial (Study A, n=409), adults with

type 1 diabetes were randomized to treatment with either LEVEMIR

at 12-hour intervals, LEVEMIR

administered in the morning and

bedtime or NPH insulin administered in the morning and bedtime.

Insulin aspart was also administered before each meal. At 16 weeks

of treatment, the combined LEVEMIR

-treated patients had similar

HbA

and fasting plasma glucose (FPG) reductions compared to the

NPH-treated patients (Table 7). Differences in timing of LEVEMIR

administration had no effect on HbA

, fasting plasma glucose

(FPG), or body weight.

In a 26-week, open-label clinical trial (Study B, n=320), adults with

type 1 diabetes were randomized to twice-daily LEVEMIR

(admin-

istered in the morning and bedtime) or once-daily insulin glargine

(administered at bedtime). Insulin aspart was administered before

each meal. LEVEMIR

-treated patients had a decrease in HbA

similar to that of insulin glargine-treated patients.

In a 24-week, open-label clinical trial (Study C, n=749), adults

with type 1 diabetes were randomized to once-daily LEVEMIR

or once-daily NPH insulin, both administered at bedtime and

in combination with regular human insulin before each meal.

LEVEMIR

and NPH insulin had a similar effect on HbA

Table 7: Type 1 Diabetes Mellitus – Adult

Study A Study B Study C

Treatment duration 16 weeks 26 weeks 24 weeks

Treatment in combination with NovoLog

(insulin aspart)

NovoLog

(insulin aspart)

Human Soluble Insulin

(regularinsulin)

Twice-daily

LEVEMIR

Twice-daily

NPH

Twice-daily

LEVEMIR

Once-daily

insulin glargine

Once-daily

LEVEMIR

Once-daily

NPH

Number of patients treated 276 133 161 159 492 257

HbA

(%)

Baseline HbA

8.6 8.5 8.9 8.8 8.4 8.3

Adj. mean change from baseline -0.8* -0.7* -0.6** -0.5** -0.1* 0.0*

LEVEMIR

– NPH

95% CI for Treatment difference

-0.2

(-0.3, -0.0)

-0.0

(-0.2, 0.2)

-0.1

(-0.3, 0.0)

Fasting blood glucose (mg/dL)

Baseline mean 209 220 153 150 213 206

Adj. mean change from baseline -44* -9* -38** -41** -30* -9*

*From an ANCOVA model adjusted for baseline value and country.

**From an ANCOVA model adjusted for baseline value and study site.

14.2 Clinical Studies in Pediatric Patients with Type 1 Diabetes

Two open-label, randomized, controlled clinical trials have been conducted in pediatric patients with type 1 diabetes. One trial (Study D) was

26 weeks in duration and enrolled patients 6 to 17 years of age. The other trial (Study I) was 52 weeks in duration and enrolled patients 2 to

16 years of age. In both trials, LEVEMIR

and NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered

before each meal. In the 26-week trial, LEVEMIR

-treated patients had a mean decrease in HbA

similar to that of NPH insulin (Table 8). In

the 52-week trial, the randomization was stratiﬁed by age (2-5 years, n=82, and 6-16 years, n=265) and the mean HbA

increased in both

treatment arms, with similar ﬁndings in the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 8).

Table 8: Type 1 Diabetes Mellitus – Pediatric

Study D Study I

Treatment duration 26 weeks 52 weeks

Treatment in combination with NovoLog

(insulin aspart) NovoLog

(insulin aspart)

Once- or Twice Daily

LEVEMIR

Once- or Twice Daily

NPH

Once- or Twice Daily

LEVEMIR

Once- or Twice Daily

NPH

Number of subjects treated 232 115 177 170

HbA

(%)

Baseline HbA

8.8 8.8 8.4 8.4

Adj. mean change from baseline -0.7* -0.8* 0.3** 0.2**

LEVEMIR

– NPH

95% CI for Treatment difference

0.1

-0.1; 0.3

0.1

-0.1; 0.4

Fasting blood glucose (mg/dL)

Baseline mean 181 181 135 141

Adj. mean change from baseline -39 -21 -10** 0**

*From an ANCOVA model adjusted for baseline value, geographical region, gender and age (covariate).

**From an ANCOVA model adjusted for baseline value, country, pubertal status at baseline and age (stratiﬁcation factor).

6LEVEMIR

(insulin detemir) injection

14.3 Clinical Studies in Adult Patients with Type 2 Diabetes

In a 24-week, open-label, randomized, clinical trial (Study E, n=476), LEVEMIR

administered twice-daily

(before breakfast and evening) was compared to NPH insulin administered twice-daily (before breakfast

and evening) as part of a regimen of stable combination therapy with one or two of the following oral

antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase inhibitor. All

patients were insulin-naïve at the time of randomization. LEVEMIR

and NPH insulin similarly lowered

HbA

from baseline (Table 9).

In a 22-week, open-label, randomized, clinical trial (Study F, n=395) in adults with type 2 diabetes,

LEVEMIR

and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with

insulin aspart. As measured by HbA

or FPG, LEVEMIR

had efﬁcacy similar to that of NPH insulin.

Table 9: Type 2 Diabetes Mellitus – Adult

Study E Study F

Treatment duration 24 weeks 22 weeks

Treatment in combination with oral agents insulin aspart

Twice-daily

LEVEMIR

Twice-daily

NPH

Once- or Twice

Daily LEVEMIR

Once- or Twice

Daily NPH

Number of subjects treated 237 239 195 200

HbA

(%)

Baseline HbA

8.6 8.5 8.2 8.1

Adj. mean change from baseline -2.0* -2.1* -0.6** -0.6**

LEVEMIR

– NPH

95% CI for Treatment difference

0.1

(-0.0, 0.3)

-0.1

(-0.2, 0.1)

Fasting blood glucose

(mg/dL)

Baseline mean 179 173 - -

Adj. mean change from baseline -69* -74* - -

Study F - Fasting blood glucose data not collected

* From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category.

**From an ANCOVA model adjusted for baseline value and country.

Combination Therapy with Metformin and Liraglutide

This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA

7-10%)

on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA

7-8.5%) on metformin

(≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued

the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on

therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients

(50%) achieved HbA

<7% with liraglutide 1.8 mg and metformin and continued treatment in a non-

randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in

period with approximately one-half of these patients doing so because of gastrointestinal adverse

reactions. The remaining 323 patients with HbA

≥7% (33% of those who entered the run-in period)

were randomized to 26 weeks of once-daily LEVEMIR

administered in the evening as add-on therapy

(n=162) or to continued, unchanged treatment with liraglutide 1.8 mg and metformin (n=161). The

starting dose of LEVEMIR

was 10 units/day and the mean dose at the end of the 26-week randomized

period was 39 units/day. During the 26-week randomized treatment period, the percentage of patients

who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment

with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with

LEVEMIR

Treatment with LEVEMIR

as add-on to liraglutide 1.8 mg + metformin resulted in statistically

signiﬁcant reductions in HbA

and FPG compared to continued, unchanged treatment with liraglutide

1.8 mg + metformin alone (Table 10). From a mean baseline body weight of 96 kg after randomization,

there was a mean reduction of 0.3 kg in the patients who received LEVEMIR

add-on therapy compared

to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide

1.8 mg + metformin alone.

Table 10: Results of a 26-week Open-label Trial of LEVEMIR

as Add-on to Liraglutide

+ Metformin Compared to Continued Treatment with Liraglutide + Metformin Alone in

Patients Not Achieving HbA

<7% After 12 Weeks of Metformin and Liraglutide

Study H

LEVEMIR

Liraglutide +

Metformin

Liraglutide +

Metformin

Intent-to-Treat Population (N)

162 157

HbA

(%) (Mean)

Baseline (week 0) 7.6 7.6

Adjusted mean change from baseline -0.5* 0*

Difference from liraglutide + metformin arm (LS mean)

95% Conﬁdence Interval

-0.5***

(-0.7, -0.4)

Percentage of patients achieving A

<7% 43** 17**

Fasting Plasma Glucose (mg/dL) (Mean)

Baseline (week 0) 166 159

Adjusted mean change from baseline -38* -7*

Difference from liraglutide + metformin arm (LS mean)

95% Conﬁdence Interval

-31***

(-39, -23)

Intent-to-treat population using last observation on study

Least squares mean adjusted for baseline value

* From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category.

**From a logistic regression model adjusted for baseline HbA

***p-value <0.0001

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

LEVEMIR

(insulin detemir) injection 100 units/mL (U-100) is a clear and colorless solution available

in the following presentations:

Presentation NDC

3 mL Single-patient-use FlexPen

pen 0169-6432-10

10 mL Multiple-dose vial 0169-3687-12

Additional Information about LEVEMIR

FlexPen

• The pen dials in 1-unit increments.

• Use NovoFine

or NovoFine Plus

disposable needles.

• Each pen for use by a single patient. LEVEMIR

FlexPen

must never be shared between patients,

even if the needle is changed.

16.2 Storage

Dispense in the original sealed carton with the enclosed Instructions for Use.

Store unused (unopened) LEVEMIR

in the refrigerator between 36° to 46°F (2° and 8°C). Do not store

in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not use LEVEMIR

if it has been frozen. Keep unused LEVEMIR

in the carton so that it stays clean and protected from light.

Remove the needle from the LEVEMIR

FlexPen

pen after each injection and store without a needle

attached. Use a new needle for each injection.

The storage conditions for vials and LEVEMIR

FlexPen

preﬁlled pens are summarized in Table 11:

Table 11: Storage Conditions for LEVEMIR

FlexPen

andVial

LEVEMIR

Presentation

Not in-use (unopened) In-use (opened)

Refrigerated

(36°F to 46°F

[2°C and 8°C])

Room

Temperature

(up to 86°F [30°C])

Refrigerated

(36°F to 46°F

[2°C and 8°C])

Room

Temperature

(up to 86°F [30°C])

3 mL single-patient-use

LEVEMIR

FlexPen

Until

expirationdate

42 days Do not refrigerate 42 days

10 mL

multiple-dose vial

Until

expirationdate

42 days 42 days 42 days

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Patient Labeling (Patient Information and Instructions for Use). There are separate

Instructions for Use for the Vials and LEVEMIR

FlexPen

Preﬁlled Pen.

Never Share a LEVEMIR

FlexPen

or Insulin Syringe Between Patients

Advise patients that they must never share a LEVEMIR

FlexPen

with another person, even if the

needle is changed. Advise patients using LEVEMIR

vials not to share needles or insulin syringes with

another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and

Precautions (5.1)].

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of

the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). This may present a risk

in situations where these abilities are especially important, such as driving or operating other machinery.

Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to

use caution when driving or operating machinery [see Warnings and Precautions (5.3)].

Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and

that changes in insulin regimen should be made under close medical supervision [see Warnings and

Precautions (5.2)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with LEVEMIR

. Inform patients on the

symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].

Hypoglycemia Due to Medication Errors

Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin

products [see Warnings and Precautions (5.4)].

Novo Nordisk

, Levemir

, NovoLog

, FlexPen

, and NovoFine

are registered trademarks of

NovoNordisk A/S.

Patent Information: https://www.novonordisk-us.com/products/product-patents.html

Manufactured by:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

U.S. License Number 1261

For information about LEVEMIR

contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, New Jersey 08536

1-800-727-6500

www.novonordisk-us.com

US22LV00025 12/2022

7LEVEMIR

(insulin detemir) injection

PATIENT INFORMATION

LEVEMIR

(LEV–uh-mere)

(insulin detemir) injection, for subcutaneous use

Do not share your LEVEMIR

FlexPen

with other people, even if the needle has been

changed. Do not share needles or syringes with another person. You may give other

people a serious infection or get a serious infection from them.

What is LEVEMIR

• LEVEMIR

is a man-made insulin that is used to control high blood sugar in adults and children

with diabetes mellitus.

• LEVEMIR

is not for people with diabetic ketoacidosis (increased ketones in the blood or urine).

Who should not take LEVEMIR

Do not take LEVEMIR

if you:

• are having an episode of low blood sugar (hypoglycemia).

• have an allergy to LEVEMIR

or any of the ingredients in LEVEMIR

. See the end of this Patient

Information leaﬂet for a complete list of ingredients in LEVEMIR

Before taking LEVEMIR

, tell your healthcare provider about all your medical

conditions including, if you:

• take any other medicines, especially medicines commonly called TZDs (thiazolidinediones).

• are pregnant, planning to become pregnant, or are breastfeeding.

Tell your healthcare provider all the medicines you take, including prescription and over-

the-counter medicines, vitamins, or herbal supplements. Before you start taking LEVEMIR

talk to your healthcare provider about low blood sugar and how to manage it.

How should I take LEVEMIR

• Read the Instructions for Use that comes with your LEVEMIR

• Take LEVEMIR

exactly as your healthcare provider tells you to.

• Know the type and strength of insulin you take. Do not change the type of insulin you take unless

your healthcare provider tells you to. The amount of insulin and the best time for you to take your

insulin may need to change if you take different types of insulin.

• Check your blood sugar levels. Ask your healthcare provider what your blood sugars should

be and when you should check your blood sugar levels.

• Do not reuse or share your needles or syringes with other people. You may give other

people a serious infection or get a serious infection from them.

• LEVEMIR

is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or

stomach area (abdomen).

• Do not inject LEVEMIR

into a vein or muscle.

• Change (rotate) your injection sites within the area you choose with each dose to

reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous

amyloidosis (skin with lumps) at the injection sites.

• Do not use the exact same spot for each injection.

• Do not inject where the skin has pits, is thickened, or has lumps.

• Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.

What should I avoid while taking LEVEMIR

While taking LEVEMIR

do not:

• Drive or operate heavy machinery, until you know how LEVEMIR

affects you.

• Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.

What are the possible side effects of LEVEMIR

LEVEMIR

may cause serious side effects that can lead to death, including:

• low blood sugar (hypoglycemia). Low blood sugar can be a serious, but common side effect

of LEVEMIR

. Signs and symptoms that may indicate low blood sugar include:

• dizziness or light-headedness • blurred vision

• anxiety, irritability, or mood changes • sweating

• slurred speech • hunger • confusion

• shakiness • headache • fast heartbeat

• severe allergic reactions. Severe allergic reactions are a potential side effect of LEVEMIR

Get emergency medical help if you have:

• trouble breathing • fast heartbeat • swelling of your face, tongue, or throat

• extreme drowsiness • dizziness • shortness of breath

• swelling • sweating • confusion

• low potassium in your blood (hypokalemia).

• heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with LEVEMIR

may

cause heart failure in some people. This can happen even if you have never had heart failure or

heart problems before. If you already have heart failure, it may get worse while you take TZDs with

LEVEMIR

. Tell your healthcare provider if you have any new or worse symptoms of heart failure

including:

• shortness of breath • swelling of ankles or feet • sudden weight gain

Treatment with TZDs and LEVEMIR

may need to be changed or stopped by your healthcare

provider if you have new or worse heart failure.

Other common side effects of LEVEMIR

include:

• injection site reactions • weight gain • rash

• skin thickening or pits at the injection site (lipodystrophy)

• swelling of your hands and feet • itching

Your insulin dose may need to change because of:

• change in level of physical activity or exercise • weight gain or loss

• increased stress • illness • change in diet

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of LEVEMIR

. Call your doctor for medical advice about

side effects. You may report side effects to FDA at 1-800-FDA-1088.

General information about the safe and effective use of LEVEMIR

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information

Leaﬂet. Do not use LEVEMIR

for a condition for which it was not prescribed. Do not give LEVEMIR

to other people, even if they have the same symptoms that you have. It may harm them. You can ask

your pharmacist or healthcare provider for information about LEVEMIR

that is written for health

professionals.

What are the ingredients in LEVEMIR

Active Ingredient: insulin detemir

Inactive Ingredients: dibasic sodium phosphate, glycerin, metacresol, phenol, sodium chloride,

zinc and Water for Injection, USP. Hydrochloric acid or sodium hydroxide may be added.

Manufactured by:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

U.S. License Number 1261

For more information, go to www.novonordisk-us.com or call 1-800-727-6500.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Revised: 12/2022

8LEVEMIR

(insulin detemir) injection

9. Turn the vial and syringe

upside down and slowly

pull the plunger back to

a few units beyond the

correct dose that you

need.

10. If there are air bubbles,

tap the syringe gently with

your ﬁnger to raise the air

bubbles to the top of the

needle. Then slowly push

the plunger to the correct

unit marking for your

dose.

11. Check to make sure you have the right dose of LEVEMIR

the syringe.

12. Pull the syringe out of the vial.

13. Inject your LEVEMIR

right away as instructed by your

healthcare provider. LEVEMIR

can be injected under the

skin (subcutaneously) of your stomach area (abdomen),

upper legs (thighs) or upper arms. For each injection, change

(rotate) your injection site within the area of skin that you use

to reduce your risk of getting lipodystrophy (pits in skin or

thickened skin) and localized cutaneous amyloidosis (skin

with lumps) at the injection sites. Do not use the same

injection site for each injection. Do not inject where the skin

has pits, is thickened, or has lumps. Do not inject where

the skin is tender, bruised, scaly or hard, or into scars or

damaged skin.

How should I inject LEVEMIR

with a syringe?

If you clean your injection site with an alcohol swab, let the

injection site dry before you inject. Talk with your healthcare

provider about how to rotate injection sites and how to give an

injection.

1. Pinch your skin between

two ﬁngers, push the

needle into the skinfold,

using a dart-like motion

and push the plunger to

inject the insulin under

your skin. The needle will

be straight in.

2. Keep the needle under your skin for at least 6 seconds to

make sure you have injected all the insulin. After you pull the

needle from your skin you may see a drop of LEVEMIR

the needle tip. This is normal and has no effect on the dose

you just received.

3. If blood appears after you pull the needle from your skin,

press the injection site lightly with an alcohol swab. Do not

rub the area.

4. After each injection, remove the needle without

recapping and dispose of it in a puncture-resistant

container. Used vials, syringes, needles, and lancets should

be placed in sharps containers (such as red biohazard

containers), hard plastic containers (such as detergent

bottles), or metal containers (such as an empty coffee can).

Such containers should be sealed and disposed of properly.

INSTRUCTIONS FOR USE

LEVEMIR

(LEV–uh-mere)

injection, for subcutaneous use

10 mL multiple-dose vial

Please read the following Instructions for use carefully before using

your LEVEMIR

vial and each time you get a reﬁll. You should read

the instructions in this manual even if you have used an insulin

vial before.

How should I use the LEVEMIR

vial?

Using the vial:

1. Check to make sure that you have the correct type of insulin.

This is especially important if you use different types of

insulin.

2. Look at the vial and the insulin. The LEVEMIR

insulin

should be clear and colorless. The tamper-resistant cap

should be in place before the ﬁrst use. If the cap has been

removed before your ﬁrst use of the vial, or if the insulin is

cloudy or colored, do not use the insulin and return it to

your pharmacy.

3. Wash your hands with soap and water.

4. If you are using a new

vial, pull off the tamper-

resistant cap.

Before each use, wipe the

rubber stopper with an

alcohol wipe.

5. Do not roll or shake the vial. Shaking the vial right before the

dose is drawn into the syringe may cause bubbles or foam.

This can cause you to draw up the wrong dose of insulin.

Theinsulin should be used only if it is clear and colorless.

6. Pull back the plunger

on your syringe until

the black tip reaches the

marking for the number of

units you will inject.

7. Push the needle through

the rubber stopper into the

vial.

8. Push the plunger all the

way in. This inserts air

into the vial.

How should I store LEVEMIR

• Do not freeze LEVEMIR

. Do not use LEVEMIR

if it has been

frozen.

• Keep LEVEMIR

away from heat or light.

• All unopened vials:

• Store unopened LEVEMIR

vials in the refrigerator at 36°F to

46°F (2°C to 8°C).

• Unopened vials may be used until the expiration date printed

on the label, if they have been stored in the refrigerator.

• Unopened vials should be thrown away after 42 days, if they

are stored at room temperature up to 86°F (30°C).

• After vials have been opened:

• Opened LEVEMIR

vials can be stored in the refrigerator at

36°F to 46°F (2°C to 8°C) or at room temperature up to 86°F

(30°C).

• Throw away all opened LEVEMIR

vials after 42 days, even if

they still have insulin left in them.

Revised: 07/2022

Novo Nordisk

and LEVEMIR

are registered trademarks of

NovoNordisk A/S.

PATENT Information: https://www.novonordisk-us.com/products/

product-patents.html

Manufactured by:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

U.S. License Number 1261

US22LV00025 12/2022

9Levemir

(insulin detemir) injection FlexPen

or has lumps. Do not inject where the skin is tender, bruised, scaly

or hard, or into scars or damaged skin.

I. Insert the needle into your skin.

Inject the dose by pressing the

green push-button all the way in

until the 0 lines up with the pointer

(see diagram I). Be careful only to

push the green push-button when

injecting.

Turning the dose selector will not

inject the insulin.

J. Keep the needle in the skin for

at least 6 seconds, and keep the

green push-button pressed all

the way in until the needle has

been pulled out from the skin (see

diagram J). This will make sure

that the full dose has been given.

You may see a drop of insulin at the needle tip. This is

normal and has no effect on the dose you just received.

Ifblood appears after you take the needle out of your skin,

press the injection site lightly with an alcohol swab. Do not

rub the area.

After the injection

Do not recap the needle. Recapping can lead to a needle stick

injury. Remove the needle from the LEVEMIR

FlexPen

after each

injection and dispose of it. This helps to prevent infection, leakage

of insulin, and will help to make sure you inject the right dose of

insulin.

• If you do not have a sharps container, carefully slip the needle

into the outer needle cap using 1 hand. Use your other hand

to pinch the base of the big outer needle cap and unscrew the

used needle from the Pen and throw it away as soon as you can.

• The used LEVEMIR

FlexPen

may be thrown away in your

household trash after you have removed the needle.

• Put your used needles in an FDA-cleared sharps disposal

container right away after use. Do not throw away (dispose of)

loose needles in your household trash.

• If you do not have a FDA-cleared sharps disposal container, you

may use a household container that is:

• made of a heavy-duty plastic,

• can be closed with a tight-ﬁtting, puncture-resistant lid,

without sharps being able to come out,

• upright and stable during use,

• leak-resistant, and

• properly labeled to warn of hazardous waste inside the

container.

• When your sharps disposal container is almost full, you will

need to follow your community guidelines for the right way to

dispose of your sharps disposal container. There may be state

or local laws about how you should throw away used needles

and syringes. For more information about the safe sharps

disposal, and for speciﬁc information about sharps disposal in

the state that you live in, go to the FDA’s website at: http://www.

fda.gov/safesharpsdisposal.

Do not dispose of your used sharps disposal container in your

household trash unless your community guidelines permit this.

Donot recycle your used sharps disposal container.

When there is not enough medicine left in your LEVEMIR

FlexPen

for your prescribed dose, the LEVEMIR

FlexPen

may

be thrown away in your household trash after you have removed

the needle.

The LEVEMIR

FlexPen

prevents the cartridge from being

completely emptied. It is designed to deliver 300 units.

K. Put the pen cap on the LEVEMIR

FlexPen

and store the LEVEMIR

FlexPen

without the needle

attached (see diagram K).

Storing without the needle attached

helps prevent leaking, blocking of

the needle, and air from entering the

LEVEMIR

FlexPen

How should I store LEVEMIR

FlexPen

• Store the unused (unopened) LEVEMIR

FlexPen

in the

refrigerator between 36°F to 46°F (2°C to 8°C).

• Store the LEVEMIR

FlexPen

you are currently using out of

the refrigerator up to 86°F.

• Do not freeze the LEVEMIR

FlexPen

. Do not use the

LEVEMIR

FlexPen

if it has been frozen.

• Keep the LEVEMIR

FlexPen

away from heat or light.

Instructions For Use

LEVEMIR

(LEV–uh-mere) FlexPen

(insulin detemir) injection, for subcutaneous use

Please read the following instructions carefully before using your

LEVEMIR

FlexPen

Do not share your LEVEMIR

FlexPen

with other

people, even if the needle has been changed. You may

give other people a serious infection or get a serious

infection from them.

LEVEMIR

FlexPen

is a preﬁlled disposable, single-patient-use,

insulin pen. You can select doses from 1 to 60 units in increments

of 1 unit. LEVEMIR

FlexPen

is designed to be used with

NovoFine

or NovoFine

Plus needles.

People who are blind or have vision problems should not use this

Pen without help from a person trained to use the Pen.

Getting ready

Make sure you have the followingitems:

• LEVEMIR

FlexPen

• NovoFine

or NovoFine

Plus disposable needles

• Alcohol swab

• Sharps disposal container (see After the Injection)

LEVEMIR

FlexPen

Pen cap

Rubber

stopper

Cartridge

scale

Pointer

Dose

selector

Push-

button

NovoFine

Big outer

needle cap

Inner needle

cap Needle

Protective

tab

NovoFine

Plus

Big outer

needle cap

Inner needle

cap Needle

Protective

tab

Preparing your LEVEMIR

FlexPen

Wash your hands with soap and water. Before you start to prepare

your injection, check the label to make sure that you are taking the

right type of insulin. This is especially important if you take more

than 1 type of insulin. LEVEMIR

should look clear and colorless.

Do not use LEVEMIR

if it is thick, cloudy, or is colored.

A. Pull off the pen cap (see diagram A).

Wipe the rubber stopper with an

alcohol swab.

B. Attaching the needle

Remove the protective tab from a

new disposable needle.

Screw the needle tightly onto

your LEVEMIR

FlexPen

. It is

important that the needle is put on

straight (see diagram B).

Never place a disposable needle on your LEVEMIR

FlexPen

until you are ready to give your injection.

C. Pull off the big outer needle cap

(see diagram C).

D. Pull off the inner needle cap and

throw it away (dispose of it) (see

diagram D).

Always use a new needle for each injection to make sure

the needle is free of germs (sterile) and to prevent blocked

needles. Do not reuse or share your needles with other

people. You may give other people a serious infection or get a

serious infection from them.

Be careful not to bend or damage the needle before use.

To reduce the risk of needle sticks, never put the inner needle

cap back on the needle.

Giving the airshot before each injection

Before each injection, small amounts of air may collect in the

cartridge during normal use. To avoid injecting air and to ensure

proper dosing:

E. Turn the dose selector to select

2units (see diagram E).

2 units

selected

F. Hold your LEVEMIR

FlexPen

with the needle pointing up. Tap

the cartridge gently with your

ﬁnger a few times to make any air

bubbles collect at the top of the

cartridge (see diagram F).

G. Keep the needle pointing upwards,

press the green push-button all the

way in (see diagram G). The dose

selector returns to 0.

A drop of insulin should appear at

the needle tip. If not, change the

needle and repeat the procedure no

more than 6 times.

If you do not see a drop of insulin

after 6 times, do not use the

LEVEMIR

FlexPen

and contact

Novo Nordisk at 1-800-727-6500.

A small air bubble may remain at the needle tip, but it will not

be injected.

Selecting your dose

Check and make sure that the dose selector is set at 0.

H. Turn the dose selector to the

number of units you need to inject.

The pointer should line up with

your dose.

The dose can be corrected either

up or down by turning the dose

selector in either direction until

the correct dose lines up with

the pointer (see diagram H).

When turning the dose selector,

be careful not to press the green

push-button as insulin will come

out.

You cannot select a dose larger

than the number of units left in the

cartridge.

24 units

selected

5 units

selected

You will hear a click for every single unit dialed. Do not set

the dose by counting the number of clicks you hear because

you may get an incorrect dose.

Do not use the cartridge scale printed on the cartridge to measure

your dose of insulin.

Giving the injection

Give the injection exactly as shown to you by your healthcare

provider. Your healthcare provider should tell you if you need to

pinch the skin before injecting. Wipe the skin with an alcohol swab

and let the area dry.

LEVEMIR

can be injected under the skin (subcutaneously) of your

stomach area (abdomen), upper legs (thighs), or upper arms.

Change (rotate) your injection sites within the area you choose for

each dose to reduce your risk of getting lipodystrophy (pits in skin

or thickened skin) and localized cutaneous amyloidosis (skin with

lumps) at the injection sites. Do not use the same injection site for

each injection. Do not inject where the skin has pits, is thickened,

10Levemir

(insulin detemir) injection FlexPen

This Instructions for Use has been approved by the U.S. Food and

Drug Administration.

Manufactured by:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

U.S. License Number 1261

Revised: 12/2022

US22LV00025 12/2022

• Unused LEVEMIR

FlexPens may be used until the expiration

date printed on the label, if kept in the refrigerator.

The LEVEMIR

FlexPen

you are using should be thrown away

after 42 days, even if it still has insulin left in it.

Keep your LEVEMIR

FlexPen

and needles out of the

reach of children.

Maintenance

For the safe and proper use of your LEVEMIR

FlexPen

be sure to

handle it with care. Avoid dropping your LEVEMIR

FlexPen

as it

may damage it. If you are concerned that your LEVEMIR

FlexPen

is damaged, use a new one. You can clean the outside of your

LEVEMIR

FlexPen

by wiping it with a damp cloth. Do not soak

or wash your LEVEMIR

FlexPen

as it may damage it. Do not

reﬁll your LEVEMIR

FlexPen

Remove the needle from the LEVEMIR

FlexPen

after each

injection. This helps to ensure sterility, prevent leakage of insulin,

and will help to make sure you inject the right dose of insulin for

future injections.

Be careful when handling used needles to avoid needle sticks

and transfer of infectious diseases. Use the LEVEMIR

FlexPen

exactly as your healthcare provider tells you to.

Do not share your LEVEMIR

FlexPen

or needles with other

people. You may give other people a serious infection, or get a

serious infection from them.

Always use a new needle for each injection.

Novo Nordisk is not responsible for harm due to using this insulin

pen with products not recommended by Novo Nordisk.

As a precautionary measure, always carry a spare insulin delivery

device in case your LEVEMIR

FlexPen

is lost or damaged.

Remember to keep the disposable LEVEMIR

FlexPen

with you.

Donot leave it in a car or other location where it can get too hot

or too cold.

11LEVEMIR

(insulin detemir) injection

INSTRUCTION FOR USE

Levemir

(LEV–uh-mere)

(insulin detemir) injection, for subcutaneous use

FlexTouch

Pen

Please read the following instructions carefully before using your

Levemir

FlexTouch

Pen.

• Do not share your Levemir

FlexTouch

Pen with other

people, even if the needle has been changed. You may

give other people a serious infection, or get a serious

infection from them.

• Levemir

FlexTouch

Pen (“Pen”) is a preﬁlled

disposable, single-patient-use insulin pen containing

300 units insulin detemir. You can inject from 1 to 80 units in a

single injection.

• People who are blind or have vision problems should

not use this Pen without help from a person trained to

use the Pen.

Supplies you will need to give your Levemir

injection:

• Levemir

FlexTouch

Pen

• a new NovoFine

, NovoFine

Plus or NovoTwist

needle

• alcohol swab

• 1 sharps container for throwing away used Pens and needles.

See “Disposing of used Levemir

FlexTouch

Pens

and needles” at the end of these instructions.

Preparing your Levemir

FlexTouch

Pen:

• Wash your hands with soap and water.

• Before you start to prepare your injection, check the

Levemir

FlexTouch

Pen label to make sure you

are taking the right type of insulin. This is especially

important if you take more than 1 type of insulin.

• Levemir

should look clear and colorless. Do not use Levemir

if it is thick, cloudy, or is colored.

• Do not use Levemir

past the expiration date printed on the

label or 42 days after you start using the Pen.

• Always use a new needle for each injection to help ensure

sterility and prevent blocked needles. Do not reuse or share

your needles with other people. You may give other

people a serious infection, or get a serious infection

from them.

ovoFine

Outer

need

le cap

Inner

needle cap

Needle

Paper

tab

ovoFine

Plus

Outer

need

le cap

Inner

needle cap

Needle

Paper

tab

ovoTwist

Outer

need

le cap

Inner

needle cap

Needle

Paper

tab

Pen cap

Levemir

FlexTouch

(insulin detemir) injection

250

200

150

100

Insulin

scale

Insulin

window

Dose

counter

Dose

selector

Dose

pointer

Dose

button

Step 1:

• Pull Pen cap straight off

(See Figure B).

(Figure B)

(Figure A)

Step 9:

• Hold the Pen with the

needle pointing up.

Press and hold in the

dose button until the dose

counter shows “0”. The

“0” must line up with the

dose pointer.

• A drop of insulin should

be seen at the needle tip

(See Figure J).

• If you do not see a

drop of insulin, repeat

steps 7 to 9, no more

than 6 times.

• If you still do not

see a drop of insulin,

change the needle and

repeat steps 7 to 9.

(Figure J)

Selecting your dose:

Step 10:

• Turn the dose selector

to select the number

of units you need to

inject. The dose pointer

should line up with your

dose (See Figure K).

• If you select the wrong

dose, you can turn the

dose selector forwards

or backwards to the

correct dose.

• The even numbers

are printed on the dial.

• The odd numbers are

shown as lines.

24 units

selected

5 units

selected

Examples

(Figure K)

• The Levemir

FlexTouch

Pen insulin scale will

show you how much

insulin is left in your Pen

(See Figure L).

250

200

150

100

Example:

Approx.

200 units

left

(Figure L)

• To see how much insulin is left in your Levemir

FlexTouch

Pen:

• Turn the dose selector until it stops. The dose counter will

line up with the number of units of insulin that is left in

your Pen. If the dose counter shows 80, there are at least

80 units left in your Pen.

• If the dose counter shows less than 80, the number

shown in the dose counter is the number of units left in

your Pen.

Step 2:

• Check the liquid in

the Pen (See Figure

C). Levemir

should

look clear and colorless.

Do not use it if it looks

cloudy or colored.

(Figure C)

Step 3:

• Select a new

needle.

• Pull off the paper tab

from the outer needle

cap (See Figure D).

NovoFine

Plus

NovoTwist

(Figure D)

Step 4:

• Push the capped

needle straight onto

the Pen and twist the

needle on until it is

tight (See Figure E).

NovoFine

Plus

NovoTwist

(Figure E)

Step 5:

• Pull off the outer

needle cap. Donot

throw it away

(SeeFigure F).

NovoFine

Plus

NovoTwist

(Figure F)

Step 6:

• Pull off the inner

needle cap and

throwit away

(SeeFigure G).

NovoFine

Plus

NovoTwist

(Figure G)

Priming your Levemir

FlexTouch

Pen:

Step 7:

• Turn the dose selector

to select 2 units

(SeeFigure H).

2 units

selected

(Figure H)

Step 8:

• Hold the Pen with the

needle pointing up. Tap

the top of the Pen gently

a few times to let any air

bubbles rise to the top

(See Figure I).

(Figure I)

12LEVEMIR

(insulin detemir) injection

Giving your injection:

• Inject your Levemir

exactly as your healthcare provider has

shown you. Your healthcare provider should tell you if you need

to pinch the skin before injecting.

• Levemir

can be injected under the skin (subcutaneously) of

your stomach area (abdomen), upper legs (thighs) or upper

arms.

• For each injection, change (rotate) your injection site within

the area of skin that you use to reduce your risk of getting

lipodystrophy (pits in skin or thickened skin) and localized

cutaneous amyloidosis (skin with lumps) at the injection sites.

Do not use the same injection site for each injection. Do not

inject where the skin has pits, is thickened, or has lumps. Do

not inject where the skin is tender, bruised, scaly or hard, or into

scars or damaged skin.

Step 11:

• Choose your injection

site (abdomen, thighs or

upper arms) and wipe the

skin with an alcohol swab.

Let the injection site dry

before you inject your

dose (See Figure M).

(Figure M)

Step 12:

• Insert the needle into

your skin (See Figure N).

• Make sure you

can see the dose

counter. Do not

cover it with your

ﬁngers; this can stop

your injection.

(Figure N)

Step 13:

• Press and hold down

the dose button until

the dose counter shows

“0” (See Figure O).

• The “0” must line up

with the dose pointer.

You may then hear or

feel a click.

• Keep the needle in

your skin after the dose

counter has returned to “0”

and slowly count to 6

(See Figure P).

• When the dose

counter returns to

“0”, you will not

get your full dose

until 6 seconds

later.

• If the needle is

removed before you

count to 6, you may

see a stream of

insulin coming from

the needle tip.

• If you see a stream

of insulin coming

from the needle

tip you will not get

your full dose. If

this happens you

should check your

blood sugar levels

more often because

you may need more

insulin.

(Figure O)

Count slowly:

1-2-3-4-5-6

(Figure P)

• Do not freeze Levemir

. Do not use Levemir

if it has been

frozen.

• Keep Levemir

away from heat or light.

• Unused Pens may be used until the expiration date printed on

the label, if kept in the refrigerator.

• The Levemir

FlexTouch

Pen you are using should be thrown

away after 42 days, even if it still has insulin left in it.

General Information about the safe and effective use of

Levemir

• Keep Levemir

FlexTouch

Pens and needles out of

the reach of children.

• Always use a new needle for each injection.

• Do not share your Levemir

FlexTouch

Pen or needles with

other people. You may give other people a serious infection, or

get a serious infection from them.

This Instructions for Use has been approved by the U.S. Food and

Drug Administration.

Manufactured by:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

U.S. License Number 1261

Revised: 07/2022

For more information go to

www.novotraining.com/levemirﬂextouch/us02

US22LV00025 12/2022

Step 14:

• Pull the needle out of

your skin (See Figure Q).

• If you see blood after

you take the needle

out of your skin, press

the injection site

lightly with a piece of

gauze or an alcohol

swab. Do not rub the

area.

(Figure Q)

Step 15:

• Carefully remove

the needle from the

Pen and throw it

away (See Figure R).

• Do not recap the

needle. Recapping

the needle can

lead to needle stick

injury.

• If you do not have

a sharps container,

carefully slip the needle

into the outer needle

cap (See Figure S).

Safely remove the

needle and throw it

away as soon as you

can.

• Do not store the

Pen with the needle

attached. Storing

without the needle

attached helps

prevent leaking,

blocking of the

needle, and air from

entering the Pen.

NovoFine

Plus

NovoTwist

(Figure R)

(Figure S)

Step 16:

• Replace the Pen cap by

pushing it straight on

(SeeFigure T).

(Figure T)

After your injection:

• The used Levemir

FlexTouch

Pen may be thrown away in your

household trash after you have removed the needle.

• You can put your used needles in a FDA-cleared sharps disposal

container right away after use. Do not throw away (dispose of)

loose needles in your household trash.

• If you do not have a FDA-cleared sharps disposal container, you

may use a household container that is:

• made of a heavy-duty plastic

• can be closed with a tight-ﬁtting, puncture-resistant lid,

without sharps being able to come out

• upright and stable during use

• leak-resistant

• properly labeled to warn of hazardous waste inside the

container

• When your sharps disposal container is almost full, you will

need to follow your community guidelines for the right way to

dispose of your sharps disposal container. There may be state or

local laws about how you should throw away used needles and

syringes. Do not reuse or share your needles or syringes with

other people. For more information about safe sharps disposal,

and for speciﬁc information about sharps disposal in the state

that you live in, go to the FDA’s website at: http://www.fda.gov/

safesharpsdisposal.

• Do not dispose of your used sharps disposal container in your

household trash unless your community guidelines permit this.

Do not recycle your used sharps disposal container.

How should I store my Levemir

FlexTouch

Pen?

• Store unused Levemir

FlexTouch

Pens in the refrigerator at

36°F to 46°F (2°C to 8°C).

• Store the Pen you are currently using out of the refrigerator up to

86°F.