FDA label c287ae5b-f510-18d0-e053-2995a90aeaf8

5 WARNINGS AND PRECAUTIONS Never Share a LEVEMIR FlexTouch between patients, even if the needle is changed ( 5.1 ). Dose adjustment and monitoring: Monitor blood glucose in all patients treated with insulin. Insulin regimens should be modified cautiously and only under medical supervision ( 5.2 ) Administration: Do not dilute or mix with any other insulin or solution. Do not administer subcutaneously via an insulin pump, intramuscularly, or intravenously because severe hypoglycemia can occur ( 5.3 ) Hypoglycemia is the most common adverse reaction of insulin therapy and may be life-threatening ( 5.4 , 6.1 ) Allergic reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur ( 5.5 ) Renal or hepatic impairment: May require adjustment of the LEVEMIR dose ( 5.6 , 5.7 ) Fluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including LEVEMIR ( 5.9 ) 5.1 Never Share a LEVEMIR FlexTouch Between Patients LEVEMIR FlexTouch must never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Dosage Adjustment and Monitoring Glucose monitoring is essential for all patients receiving insulin therapy. Changes to an insulin regimen should be made cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in the insulin dose or an adjustment of concomitant anti-diabetic treatment. As with all insulin preparations, the time course of action for LEVEMIR may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the local blood supply, local temperature, and physical activity. 5.3 Administration LEVEMIR should only be administered subcutaneously. Do not administer LEVEMIR intravenously or intramuscularly. The intended duration of activity of LEVEMIR is dependent on injection into subcutaneous tissue. Intravenous or intramuscular administration of the usual subcutaneous dose could result in severe hypoglycemia [see Warnings and Precautions (5.4)] . Do not use LEVEMIR in insulin infusion pumps. Do not dilute or mix LEVEMIR with any other insulin or solution. If LEVEMIR is diluted or mixed, the pharmacokinetic or pharmacodynamic profile (e.g., onset of action, time to peak effect) of LEVEMIR and the mixed insulin may be altered in an unpredictable manner. 5.4 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin therapy, including LEVEMIR. The risk of hypoglycemia increases with intensive glycemic control. 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) ] . All patients must be educated to recognize and manage hypoglycemia. Severe hypoglycemia can lead to unconsciousness or convulsions and may result in temporary or permanent impairment of brain function or death. Severe hypoglycemia requiring the assistance of another person or parenteral glucose infusion, or glucagon administration has been observed in clinical trials with insulin, including trials with LEVEMIR. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations. Other factors such as changes in food intake (e.g., amount of food or timing of meals), exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions (7)] . The prolonged effect of subcutaneous LEVEMIR may delay recovery from hypoglycemia. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., the pediatric population and patients who fast or have erratic food intake). The patient's ability to concentrate and react may be impaired as a result of hypoglycemia. This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic neuropathy, use of medications such as beta-blockers, or intensified glycemic control [see Drug Interactions (7)] . These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patient’s awareness of hypoglycemia. 5.5 Hypersensitivity and Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LEVEMIR. 5.6 Renal Impairment No difference was observed in the pharmacokinetics of insulin detemir 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 insulin, including LEVEMIR, may be necessary in patients with renal impairment [see Clinical Pharmacology (12.3)] . 5.7 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 insulin, including LEVEMIR, may be necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3)] . 5.8 Drug Interactions Some medications may alter insulin requirements and subsequently increase the risk for hypoglycemia or hyperglycemia [see Drug Interactions (7)] . 5.9 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 (5.4)] Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)] 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 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 the LEVEMIR add-on to liraglutide+metformin trial, all patients received liraglutide 1.8 mg + metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only those patients who completed the run-in period with inadequate glycemic control were randomized to 26 weeks of add-on therapy with LEVEMIR or continued, unchanged treatment with liraglutide 1.8 mg + metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in ≥5% of patients treated with liraglutide 1.8 mg + metformin (11.7%) and greater than in patients treated with liraglutide 1.8 mg and metformin alone (6.9%). In two pooled trials, a total of 1155 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 (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%) LEVEMIR, % (n = 767) NPH, % (n = 388) Upper respiratory tract infection 26.1 21.4 Headache 22.6 22.7 Pharyngitis 9.5 8.0 Influenza-like illness 7.8 7.0 Abdominal Pain 6.0 2.6 A total of 320 adults with type 1 diabetes were exposed to individualized doses of 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 (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%) LEVEMIR, % (n = 161) Glargine, % (n = 159) Upper respiratory tract infection 26.7 32.1 Headache 14.3 19.5 Back pain 8.1 6.3 Influenza-like illness 6.2 8.2 Gastroenteritis 5.6 4.4 Bronchitis 5.0 1.9 In two pooled trials, a total of 869 adults with type 2 diabetes were exposed to individualized doses of 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 are summarized in Table 3. Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%) LEVEMIR, % (n = 432) NPH, % (n = 437) Upper respiratory tract infection 12.5 11.2 Headache 6.5 5.3 A total of 347 children and adolescents (6-17 years) 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 4. Table 4: Adverse reactions (excluding hypoglycemia) in one 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%) LEVEMIR, % (n = 232) NPH, % (n = 115) Upper respiratory tract infection 35.8 42.6 Headache 31.0 32.2 Pharyngitis 17.2 20.9 Gastroenteritis 16.8 11.3 Influenza-like illness 13.8 20.9 Abdominal pain 13.4 13.0 Pyrexia 10.3 6.1 Cough 8.2 4.3 Viral infection 7.3 7.8 Nausea 6.5 7.0 Rhinitis 6.5 3.5 Vomiting 6.5 10.4 Pregnancy A randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1 diabetes. [see Use in Specific Populations (8.1)] Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR [see Warnings and Precautions (5.4)] . Tables 5 and 6 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 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. The rates of hypoglycemia in the LEVEMIR clinical trials (see Section 14 for a description of the study designs) were comparable between LEVEMIR-treated patients and non-LEVEMIR-treated patients (see Tables 5 and 6) . 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 Twice-Daily NPH 10.6 (14/132) 0.43 89.4 (118/132) 37.5 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 Once-Daily Glargine 10.1 (16/159) 0.31 77.4 (123/159) 21.8 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 Once-Daily NPH 10.2 (26/256) 0.32 87.9 (225/256) 33.4 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 Once- or Twice Daily NPH 20.0 (23/115) 0.99 95.7 (110/115) 37.0 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 Once- or Twice Daily NPH 7.1 (12/170) 0.09 97.6 (166/170) 70.7 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 Twice-Daily NPH Once- or Twice Daily LEVEMIR Once- or Twice Daily NPH Once Daily LEVEMIR + Liraglutide + Metformin Liraglutide + Metformin Severe hypoglycemia Percent of patients with at least 1 event (n/total N) 0.4 (1/237) 2.5 (6/238) 1.5 (3/195) 4.0 (8/199) 0 0 Event/patient/year 0.01 0.08 0.04 0.13 0 0 Non-severe hypoglycemia Percent of patients (n/total N) 40.5 (96/237) 64.3 (153/238) 32.3 (63/195) 32.2 (64/199) 9.2 (15/163) 1.3 (2/158 One subject is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a history of frequent hypoglycemia prior to the study ) Event/patient/year 3.5 6.9 1.6 2.0 0.29 0.03 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. Rotate insulin injection sites within the same region to reduce the risk of lipodystrophy [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) ] . Peripheral Edema Insulin, including LEVEMIR, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Allergic Reactions Local Allergy As with any insulin therapy, 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%) compared to one patient treated with NPH insulin (0.12%). The reports of pain at the injection site did not result in discontinuation of therapy. Rotation of the injection site within a given area from one injection to the next may help to reduce or prevent these reactions. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Most minor reactions to insulin usually resolve in a few days to a few weeks. Systemic Allergy 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 [see Warnings and Precautions (5.5)] . Antibody Production 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 phase 3 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 during post-approval use of LEVEMIR in which other insulins, particularly rapid-acting or short-acting insulins, have been accidentally administered instead of LEVEMIR [see Patient Counseling Information (17)] . To avoid medication errors between LEVEMIR and other insulins, patients should be instructed always to verify the insulin label before each injection.

<table ID="_Refid_33c4f35a-2ff0-471f-a0d0-361a21186" width="100%"><caption>Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence &#x2265; 5%)</caption><col width="48%"/><col width="26%"/><col width="26%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">LEVEMIR, %</content></paragraph><paragraph><content styleCode="bold">(n = 767)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">NPH, %</content></paragraph><paragraph><content styleCode="bold">(n = 388)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper respiratory tract infection</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>21.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>22.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>22.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Pharyngitis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>9.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Influenza-like illness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7.8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>7.0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Abdominal Pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2.6</paragraph></td></tr></tbody></table>

<table ID="_Refid_5ee17cb9-3172-408a-8760-aec073bf4" width="100%"><caption>Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence &#x2265; 5%)</caption><col width="48%"/><col width="26%"/><col width="26%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">LEVEMIR, %</content></paragraph><paragraph><content styleCode="bold">(n = 161)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Glargine, %</content></paragraph><paragraph><content styleCode="bold">(n = 159)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper respiratory tract infection</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26.7</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>32.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>14.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>19.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Back pain</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Influenza-like illness</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.2</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Gastroenteritis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4.4</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Bronchitis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.0</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1.9</paragraph></td></tr></tbody></table>

<table ID="_RefID0EXNAE" width="100%"><caption>Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence &#x2265; 5%)</caption><col width="48%"/><col width="27%"/><col width="26%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">LEVEMIR, %</content></paragraph><paragraph><content styleCode="bold">(n = 432)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">NPH, %</content></paragraph><paragraph><content styleCode="bold">(n = 437)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Upper respiratory tract infection</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11.2</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6.5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5.3</paragraph></td></tr></tbody></table>