LEVEMIR- insulin detemir injection, solution

Levemir by

Drug Labeling and Warnings

Levemir by is a Prescription medication manufactured, distributed, or labeled by Novo Nordisk. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

• 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 subcutaneous use
  Initial U.S. Approval: 2005

  RECENT MAJOR CHANGES

  Dosage and Administration (2.1) 11/2019

  Warnings and Precautions (5.2) 11/2019

  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 treating 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).

  DOSAGE FORMS AND STRENGTHS

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

  • 3 mL single-patient-use LEVEMIR FlexTouch ® prefilled pen (3)
  • 10 mL multiple-dose vial (3)

  CONTRAINDICATIONS

  • During episodes of hypoglycemia (4)
  • Hypersensitivity to LEVEMIR or any of its excipients (4)

  WARNINGS AND PRECAUTIONS

  • Never Share a LEVEMIR FlexTouch 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, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia 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 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 associated with LEVEMIR include hypoglycemia, 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 Increase Hypoglycemia Risk or Increase or Decrease Blood Glucose Lowering Effect: Adjustment of dosage may be needed; closely monitor blood glucose (7).
  • Drugs that Blunt Hypoglycemia Signs and Symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Increased frequency of glucose monitoring may be required (7).

  See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

  Revised: 3/2020

• Table of Contents

  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 LEVEMIR 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 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 Type 1 Diabetes - Adult

  14.2 Type 1 Diabetes - Pediatric

  14.3 Type 1 Diabetes - Pregnancy

  14.4 Type 2 Diabetes - Adult

  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.

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 lipodystrophy 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)].
• Use LEVEMIR FlexTouch with caution in patients with visual impairment who may rely on audible clicks to dial their dose.
• Do not dilute or mix LEVEMIR with any other insulin or solution.
• Do not administer LEVEMIR intravenously or in an insulin infusion pump.

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.
• LEVEMIR FlexTouch dials in 1-unit increments.
• 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

• 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.
• 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 Starting Dose in Patients Already on Insulin Therapy

• 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 unit per mL (U-100), is a clear, colorless, solution available as:

• 3 mL single-patient-use LEVEMIR FlexTouch prefilled pen
• 10 mL multiple-dose vial

4 CONTRAINDICATIONS

LEVEMIR is contraindicated:

• During episodes of hypoglycemia [see Warnings and Precautions (5.3)]
• In patients with hypersensitivity to LEVEMIR or any of its excipients. 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 FlexTouch Pen, Needle, or Syringe between Patients

LEVEMIR FlexTouch 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, manufacturer, 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 lipodystrophy 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 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). 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 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 LEVEMIR 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)]. 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 basal insulin products and other insulins, particularly rapid-acting insulins, 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 and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR. If hypersensitivity reactions occur, discontinue LEVEMIR; treat per standard of care and monitor until symptoms and signs resolve. LEVEMIR is contraindicated in patients who have had hypersensitivity reactions to insulin detemir or any of the excipients [see Contraindications (4)].

5.6 Hypokalemia

All insulin products, 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, particularly 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)]
• 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 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.

• 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.

• 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 reactions are summarized in Table 3.

• 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

Adverse reactions in pregnant patients occurring at an incidence of ≥5% are shown in Table 4. The two most common adverse reactions were nasopharyngitis and headache. These are consistent with findings from other type 1 diabetes trials (see Table 1, Section 6.1.), and are not repeated in Table 4.

The incidence of adverse reactions of pre-eclampsia was 10.5% (16 cases) and 7.0% (11 cases) in the LEVEMIR and NPH insulin groups respectively. Out of the total number of cases of pre-eclampsia, eight (8) cases in the LEVEMIR group and 1 case in the NPH insulin group required hospitalization. The rates of pre-eclampsia observed in the study are within expected rates for pregnancy complicated by diabetes. Pre-eclampsia is a syndrome defined by symptoms, hypertension and proteinuria; the definition of pre-eclampsia was not standardized in the trial making it difficult to establish a link between a given treatment and an increased risk of pre-eclampsia. All events were considered unlikely related to trial treatment. In all nine (9) cases requiring hospitalization the women had healthy infants. Events of hypertension, proteinuria and edema were reported less frequently in the LEVEMIR group than in the NPH insulin group as a whole. There was no difference between the treatment groups in mean blood pressure during pregnancy and there was no indication of a general increase in blood pressure.

In the NPH insulin group there were 6 serious adverse reactions in four mothers of the following placental disorders, ‘Placenta previa’, ‘Placenta previa hemorrhage’, and ‘Premature separation of placenta’ and 1 serious adverse reaction of ‘Antepartum haemorrhage’. There were none reported in the LEVEMIR group.

The incidence of early fetal death (abortions) was similar in LEVEMIR and NPH treated patients; 6.6% and 5.1%, respectively. The abortions were reported under the following terms: ‘Abortion spontaneous’, ‘Abortion missed’, ‘Blighted ovum’, ‘Cervical incompetence’ and ‘Abortion incomplete’.

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).

No differences in pregnancy outcomes or the health of the fetus and newborn were seen with LEVEMIR use.

Table 4: Adverse Reactions During Pregnancy in a Trial Comparing Insulin Aspart + LEVEMIR to Insulin Aspart + NPH Insulin in Pregnant Women with Type 1 Diabetes (Adverse Reactions with Incidence ≥ 5%)

• Anemia:

  13.2

• Diarrhea:

  11.8

• Pre-eclampsia:

  10.5

• Urinary tract infection:

  9.9

• Gastroenteritis:

  8.6

• Abdominal pain upper:

  5.9

• Vomiting:

  5.3

• Abortion spontaneous:

  5.3

• Abdominal pain:

  5.3

• Oropharyngeal pain:

  5.3

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR. 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 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 5 (type 1 diabetes) and Table 6 (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, including the trial in pregnant women (study G), and pediatric Study D, non-severe hypoglycemia 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 asymptomatic 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.

Table 5: 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
Study G Type 1 Diabetes Pregnancy In combination with insulin aspart	Once- or Twice Daily LEVEMIR	16.4 (25/152)	1.1	94.7 (144/152)	114.2

Table 6: 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)	0
	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

•   Allergic Reactions
•   Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any 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 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)].

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 other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered 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 7 includes clinically significant drug interactions with LEVEMIR.

Table 7: 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, pentoxifylline, pramlintide, 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 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 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 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:		Dose 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 attributed to LEVEMIR were observed [see Adverse Reactions (6.1)and Clinical Studies (14)]. 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).

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, 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

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 embryofetal development studies that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity 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 type 1 and type 2 diabetes mellitus have been established in pediatric patients.

The use of LEVEMIR for this indication is supported by evidence from an adequate and well-controlled study 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 (14.4)].

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 elderly patients, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the elderly.

8.6 Renal Impairment

No difference was observed in the pharmacokinetics of LEVEMIR between non-diabetic individuals with renal impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with renal impairment. Careful glucose monitoring and dose adjustments of LEVEMIR, may be necessary in patients with renal impairment[see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Non-diabetic individuals 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 dose 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 can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes 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 recurrence of hypoglycemia. Hypokalemia must be corrected appropriately.

11 DESCRIPTION

LEVEMIR (insulin detemir injection) is a solution for subcutaneous use. Insulin detemir is a long-acting recombinant human insulin analog. LEVEMIR is 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 C267H402O76N64S6 and a molecular weight of 5916.9. It has the following structure:

Figure 1: Structural Formula of Insulin Detemir

LEVEMIR is a clear, colorless, aqueous, neutral sterile solution. Each milliliter of LEVEMIR contains 100 units (14.2 mg/mL) insulin detemir, 65.4 mcg zinc, 2.06 mg m-cresol, 16.0 mg glycerol, 1.80 mg phenol, 0.89 mg disodium phosphate dihydrate, 1.17 mg sodium chloride, and water for injection. 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: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study

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.

Figure 3: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study

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 (Cmax) reached between 6-8 hours post-dose. Insulin detemir was more slowly absorbed after subcutaneous administration to the thigh where AUC0-5h was 30-40% lower and AUC0-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 LEVEMIRwere 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 Cmax 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-dependent). In this study, there were no differences in the pharmacokinetics 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 pharmacodynamics 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 studies 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 study 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 HbA1c with LEVEMIR was similar to that with NPH insulin or insulin glargine.

14.1 Type 1 Diabetes - Adult

In a 16-week open-label clinical study (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 HbA1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 8). Differences in timing of LEVEMIR administration had no effect on HbA1c, fasting plasma glucose (FPG), or body weight.

In a 26-week, open-label clinical study (Study B, n=320), adults with type 1 diabetes were randomized to twice-daily LEVEMIR (administered 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 HbA1c similar to that of insulin glargine-treated patients.

In a 24-week, open-label clinical study (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 HbA1c.

Table 8: 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
HbA1c (%)
Baseline HbA1c	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 Type 1 Diabetes - Pediatric

Two open-label, randomized, controlled clinical studies have been conducted in pediatric patients with type 1 diabetes. One study was 26 weeks in duration and enrolled patients 6 to 17 years of age. The other study was 52 weeks in duration and enrolled patients 2 to 16 years of age. In both studies, LEVEMIR and NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each meal. In the 26-week study, LEVEMIR-treated patients had a mean decrease in HbA1c similar to that of NPH insulin (Table 9). In the 52-week study, the randomization was stratified by age (2-5 years, n=82, and 6-16 years, n=265) and the mean HbA1c 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 9).

Table 9: 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
HbA1c (%)
Baseline HbA1c	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).

14.3 Type 1 Diabetes - Pregnancy

In an open-label clinical study, women with type 1 diabetes who were (between weeks 8 and 12 of gestation) or intended to become pregnant were randomized 1:1 to LEVEMIR (once or twice daily) or NPH insulin (once, twice or thrice daily). Insulin aspart was administered before each meal. A total of 152 women in the LEVEMIR arm and 158 women in the NPH arm were or became pregnant during the study (Total pregnant women = 310). Approximately one half of the study participants 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. In the 310 pregnant women, the mean glycosylated hemoglobin (HbA1c) was

<7% at 10, 12, and 24 weeks of gestation in both arms. In the intent-to-treat population, the adjusted mean HbA1c (standard error) at gestational week 36 was 6.27% (0.053) in LEVEMIR-treated patient (n=138) and 6.33% (0.052) in NPH-treated patients (n=145); the difference was not clinically significant.

14.4 Type 2 Diabetes - Adult

In a 24-week, open-label, randomized, clinical study (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 HbA1c from baseline (Table 10).

In a 22-week, open-label, randomized, clinical study (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 HbA1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin.

Table 10: 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
HbA1c (%)
Baseline HbA1c	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 glucose1 (mg/dL)
Baseline mean	179	173	-	-
Adj. mean change from baseline	-69*	-74*	-	-

1Study 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 (HbA1c 7-10%) on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 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 HbA1c <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 HbA1c ≥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 HbA1c and FPG compared to continued, unchanged treatment with liraglutide 1.8 mg + metformin alone (Table 11). 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 11: 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 HbA1c < 7% After 12 Weeks of Metformin and Liraglutide

	Study H
	LEVEMIR + Liraglutide +Metformin	Liraglutide+ Metformin
Intent-to-Treat Population (N)a	162	157
HbA1c (%) (Mean)
Baseline (week 0)	7.6	7.6
Adjusted mean change from baseline	-0.5*	0*
Difference from liraglutide + metformin arm (LS mean)b 95% Confidence Interval	-0.5*** (-0.7, -0.4)
Percentage of patients achieving A1c <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)b 95% Confidence Interval	-31*** (-39, -23)

aIntent-to-treat population using last observation on study

bLeast 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 HbA1c.

***p-value <0.0001

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

LEVEMIR is available as a clear and colorless solution containing 100 units of insulin detemir per mL (U-100) in the following presentations:

Presentation	Total Volume	NDC
Single-patient-use FlexTouch pen	3 mL	0169-6438-10
Multiple-dose vial	10 mL	0169-3687-12

FlexTouch can be used with NovoFine® or NovoTwist® disposable needles. Each FlexTouch is for use by a single patient. LEVEMIR FlexTouch must never be shared between patients, even if the needle is changed.

LEVEMIR FlexTouch dials in 1-unit increments.

16.2 Storage

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

Unused (unopened) LEVEMIR should be stored 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 FlexTouch pen after each injection and store without a needle attached. Use a new needle for each injection.

The storage conditions for vials and LEVEMIR FlexTouch pens are summarized in Table 12:

Table 12: Storage Conditions for LEVEMIR FlexTouch and Vial

LEVEMIR Presentation	Not in-use (unopened)		In-use (opened)
	Refrigerated (36° to 46°F [2° and 8°C])	Room Temperature (below 86°F [30°C])	Refrigerated (36° to 46°F [2° and 8°C])	Room Temperature; (below 86°F [30°C])
3 mL single-patient-use LEVEMIR FlexTouch pen	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)

Never Share a LEVEMIR FlexTouch between Patients

Advise patients that they must never share a LEVEMIR FlexTouch pen with another person, even if the needle is changed. Advise patients using LEVEMIR vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].

Hypoglycemia

Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of LEVEMIR therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia.

Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. 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)].

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)].

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®, FlexTouch®, NovoFine®, and NovoTwist® are registered trademarks of Novo Nordisk A/S.

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

© 2005-2020 Novo Nordisk

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

For information about LEVEMIR contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, New Jersey 08536

1-800-727-6500

www.novonordisk-us.com

Patient Information

Patient Information

LEVEMIR® (LEV–uh-mere)

(insulin detemir injection)

Do not share your Levemir FlexTouch 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.

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 meant for use to treat diabetic ketoacidosis.

Who should not take Levemir?

Do not take Levemir if you:

• have an allergy to Levemir or any of the ingredients in Levemir.

Before taking Levemir, tell your healthcare provider about all your medical conditions including, if you are:

• pregnant, planning to become pregnant, or are breastfeeding.
• taking new prescription or 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 come 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).
• Never 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.
• o Do not use the exact same spot for each injection.
• o Do not inject where the skin has pits, is thickened, or has lumps.
• o 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). Signs and symptoms that may indicate low blood sugar include:

• dizziness or light-headedness
• sweating
• confusion
• headache
• blurred vision
• slurred speech
• shakiness
• fast heart beat
• anxiety, irritability, or mood changes
• hunger

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

Other common side effects of Levemir may include:

• Reactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet.

Get emergency medical help if you have:

• trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.

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.

What are the ingredients in Levemir?

Active Ingredient: insulin detemir

Inactive Ingredients: zinc, m-cresol, glycerol, phenol, disodium phosphate dihydrate, sodium chloride and water for injection. Hydrochloric acid or sodium hydroxide may be added.

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

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: 11/2019

Patient Instructions For Use

 LEVEMIR® 10 mL multiple-dose vial

Please read the following Instructions for use carefully before using your LEVEMIR® 10 mL vial and each time you get a refill. You should read the instructions in this manual even if you have used an insulin 10 mL vial before.

How should I use the LEVEMIR 10 mL vial?

Using the 10 mL vial:

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.

Revised: 11/2019

Novo Nordisk® and LEVEMIR® are registered trademarks of Novo Nordisk A/S.

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

© 2005-2019 Novo Nordisk

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

For information about LEVEMIR® contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, New Jersey 08536

Instructions for Use

Levemir® (LEV–uh-mere) FlexTouch® Pen

(insulin detemir injection)

• 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 pen containing 300 units of U-100 Levemir (insulin detemir injection) insulin. 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.

Priming your Levemir FlexTouch Pen:

Selecting your dose:

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.

After your injection:

• You can put your used Levemir FlexTouch Pen and needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and Pens in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
  • o made of a heavy-duty plastic
  • o can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out
  • o upright and stable during use
  • o leak-resistant
  • o 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 below 86°F.
• 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 A/S
DK-2880 Bagsvaerd, Denmark

Revised: 11/2019

For more information go to

www.novotraining.com/levemirflextouch/us02

© 2005-2019 Novo Nordisk

Levemir®

FlexTouch®

Read before first use

Package Label - Principal Display Panel - 10 mL Vial

Levemir®

Insulin detemir injection

NDC: 0169-3687-12

List 368712

100 units/mL (U-100)

For subcutaneous use only

Rx Only

One 10 mL Vial

novo nordisk®

Package Label - Principal Display Panel – 3 mL FlexTouch

NDC: 0169-6438-10 List 643810

Levemir® FlexTouch®

Insulin detemir injection

For Single Patient Use Only

100 units/mL (U-100)

5x3 mL Prefilled Pens

For subcutaneous use only

Rx Only

Recommended for use with

NovoFine®, NovoFine® Plus or

NovoTwist® disposable needles.

Keep in a cold place until first use.

Store at 2° - 8°C (36° - 46°F).

Avoid freezing.

Protect from light.

Dispense in this sealed carton.

INGREDIENTS AND APPEARANCE

LEVEMIR 
insulin detemir injection, solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0169-3687
Route of Administration	SUBCUTANEOUS

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
INSULIN DETEMIR (UNII: 4FT78T86XV) (INSULIN DETEMIR - UNII:4FT78T86XV)	INSULIN DETEMIR	100 [iU]  in 1 mL

Inactive Ingredients
Ingredient Name	Strength
HYDROCHLORIC ACID (UNII: QTT17582CB)
GLYCERIN (UNII: PDC6A3C0OX)	16 mg  in 1 mL
METACRESOL (UNII: GGO4Y809LO)	2.06 mg  in 1 mL
PHENOL (UNII: 339NCG44TV)	1.8 mg  in 1 mL
SODIUM CHLORIDE (UNII: 451W47IQ8X)	1.17 mg  in 1 mL
SODIUM HYDROXIDE (UNII: 55X04QC32I)
ZINC (UNII: J41CSQ7QDS)	65.4 ug  in 1 mL
SODIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: 94255I6E2T)	0.89 mg  in 1 mL

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 0169-3687-12	1 in 1 CARTON	03/27/2006
1		10 mL in 1 VIAL, GLASS; Type 0: Not a Combination Product

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA021536	03/27/2006

LEVEMIR 
insulin detemir injection, solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 0169-6438
Route of Administration	SUBCUTANEOUS

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
INSULIN DETEMIR (UNII: 4FT78T86XV) (INSULIN DETEMIR - UNII:4FT78T86XV)	INSULIN DETEMIR	100 [iU]  in 1 mL

Inactive Ingredients
Ingredient Name	Strength
ZINC (UNII: J41CSQ7QDS)	65.4 ug  in 1 mL
METACRESOL (UNII: GGO4Y809LO)	2.06 mg  in 1 mL
GLYCERIN (UNII: PDC6A3C0OX)	16.0 mg  in 1 mL
PHENOL (UNII: 339NCG44TV)	1.80 mg  in 1 mL
SODIUM CHLORIDE (UNII: 451W47IQ8X)	1.17 mg  in 1 mL
HYDROCHLORIC ACID (UNII: QTT17582CB)
SODIUM HYDROXIDE (UNII: 55X04QC32I)
SODIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: 94255I6E2T)	0.89 mg  in 1 mL

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 0169-6438-10	5 in 1 CARTON	10/31/2013
1		3 mL in 1 SYRINGE, PLASTIC; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)
2	NDC: 0169-6438-97	1 in 1 CARTON	10/31/2013	12/31/2016
2	NDC: 0169-6438-90	3 mL in 1 SYRINGE, PLASTIC; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)
3	NDC: 0169-6438-98	1 in 1 CARTON	10/31/2013
3	NDC: 0169-6438-90	3 mL in 1 SYRINGE, PLASTIC; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
BLA	BLA021536	10/31/2013

Labeler - Novo Nordisk (622920320)