Levemir

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • Hypoglycemia Due to Medication errors [see Warnings and Precautions ( 5.4 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] • Hypokalemia [see Warnings and Precautions ( 5.6 )] 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 two pooled trials, adults with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=767) or NPH (n=388). The mean duration of exposure to LEVEMIR was 153 days, and the total exposure to LEVEMIR was 321 patient-years. The most common adverse reactions are summarized in Table 1. Table 1: Adverse Reactions Occurring in ≥ 5% of LEVEMIR-Treated Adult Patients with Type 1 Diabetes Mellitus in Two Trials of 16 Weeks and 24 Weeks Duration LEVEMIR, % (n = 767) Upper respiratory tract infection 26.1 Headache 22.6 Pharyngitis 9.5 Influenza-like illness 7.8 Abdominal Pain 6.0 Adults with type 1 diabetes were exposed to LEVEMIR (n=161) or insulin glargine (n=159). The mean duration of exposure to LEVEMIR was 176 days, and the total exposure to LEVEMIR was 78 patient-years. The most common adverse reactions are summarized in Table 2. Table 2: Adverse Reactions Occurring in ≥ 5% of LEVEMIR-Treated Adult Patients with Type 1 Diabetes Mellitus in a 26-week Trial LEVEMIR, % (n = 161) Upper respiratory tract infection 26.7 Headache 14.3 Back pain 8.1 Influenza-like illness 6.2 Gastroenteritis 5.6 Bronchitis 5.0 In two pooled trials, adults with type 2 diabetes were exposed to LEVEMIR (n=432) or NPH (n=437). The mean duration of exposure to LEVEMIR was 157 days, and the total exposure to LEVEMIR was 186 patient-years. The most common adverse reactions were comparable to that observed in adult patients with type 1 diabetes mellitus; see Table 1. Pediatric patients with type 1 diabetes were exposed to individualized doses of LEVEMIR (n=232) or NPH (n=115). The mean duration of exposure to LEVEMIR was 180 days, and the total exposure to LEVEMIR was 114 patient-years. The most common adverse reactions are summarized in Table 3. Table 3: Adverse Reactions Occurring in ≥ 5% of LEVEMIR-Treated Pediatric Patients with Type 1 Diabetes Mellitus in a 26-week Trial LEVEMIR, % (n = 232) Upper respiratory tract infection 35.8 Headache 31.0 Pharyngitis 17.2 Gastroenteritis 16.8 Influenza-like illness 13.8 Abdominal pain 13.4 Pyrexia 10.3 Cough 8.2 Viral infection 7.3 Nausea 6.5 Rhinitis 6.5 Vomiting 6.5 Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with LEVEMIR. The rates of reported 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 4 (type 1 diabetes) and Table 5 (type 2 diabetes) summarize the incidence of severe and non-severe hypoglycemia in the LEVEMIR clinical trials. For the adult trials and one of the pediatric trials (Study D), severe hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring assistance of another person and associated with either a plasma glucose value below 56 mg/dL (blood glucose below 50 mg/dL) or prompt recovery after oral carbohydrate, intravenous glucose or glucagon administration. For the other pediatric trial (Study I), severe hypoglycemia was defined as an event with semi-consciousness, unconsciousness, coma and/or convulsions in a patient who could not assist in the treatment and who may have required glucagon or intravenous glucose. For the adult trials and pediatric trial (Study D), non-severe 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 4: Hypoglycemia in Patients with Type 1 Diabetes Severe Hypoglycemia Non-Severe Hypoglycemia Percent of patients with at least 1 event (n/total N) Event/patient/ year Percent of patients (n/total N) Event/patient/ year Study A Type 1 Diabetes Adults 16 weeks In combination with insulin aspart Twice-Daily LEVEMIR 8.7 (24/276) 0.52 88.0 (243/276) 26.4 Study B Type 1 Diabetes Adults 26 weeks In combination with insulin aspart Twice-Daily LEVEMIR 5.0 (8/161) 0.13 82.0 (132/161) 20.2 Study C Type 1 Diabetes Adults 24 weeks In combination with regular insulin Once-Daily LEVEMIR 7.5 (37/491) 0.35 88.4 (434/491) 31.1 Study D Type 1 Diabetes Pediatrics 26 weeks In combination with insulin aspart Once- or Twice Daily LEVEMIR 15.9 (37/232) 0.91 93.1 (216/232) 31.6 Study I Type 1 Diabetes Pediatrics 52 weeks In combination with insulin aspart Once- or Twice Daily LEVEMIR 1.7 (3/177) 0.02 94.9 (168/177) 56.1 Table 5: Hypoglycemia in Patients with Type 2 Diabetes Study E Type 2 Diabetes Adults 24 weeks In combination with oral agents Study F Type 2 Diabetes Adults 22 weeks In combination with insulin aspart Study H Type 2 Diabetes Adults 26 weeks in combination with Liraglutide and Metformin Twice-Daily LEVEMIR Once- or Twice Daily LEVEMIR Once Daily LEVEMIR + Liraglutide + Metformin Severe hypoglycemia Percent of patients with at least 1 event (n/total N) 0.4 (1/237) 1.5 (3/195) 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 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including LEVEMIR, and may be life-threatening. Insulin Initiation and Intensification of Glucose Control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Lipodystrophy Long-term use of insulin, including LEVEMIR, can cause 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 rapid-acting or short-acting insulins and other 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.

4 CONTRAINDICATIONS LEVEMIR is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions (5.3)] • In patients with hypersensitivity to insulin detemir or any of the excipients in LEVEMIR. Reactions have included anaphylaxis [ see Warnings and Precautions (5.5) and Adverse Reactions (6.1) ] . • During episodes of hypoglycemia ( 4 ) • Hypersensitivity to insulin detemir or any of the excipients in LEVEMIR ( 4 )

11 DESCRIPTION Insulin detemir is a long-acting recombinant human insulin analog produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin detemir differs from human insulin in that the amino acid threonine in position B30 has been omitted, and a C14 fatty acid chain has been attached to the amino acid B29. Insulin detemir has a molecular formula of C 267 H 402 O 76 N 64 S 6 and a molecular weight of 5.917 kDa. It has the following structure: Figure 1: Structural Formula of Insulin Detemir LEVEMIR (insulin detemir) injection is a clear, colorless, aqueous, neutral sterile solution for subcutaneous use. Each milliliter of LEVEMIR contains 100 units insulin detemir, dibasic sodium phosphate (0.71 mg), glycerin (16 mg), metacresol (2.06 mg), phenol (1.8 mg), sodium chloride (1.17 mg), zinc (65.4 mcg), and Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. LEVEMIR has a pH of approximately 7.4. Levemir Chemical Structure.jpg

2 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 ). 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 )]. • Do not dilute or mix LEVEMIR with any other insulin or solution. • Do not administer LEVEMIR intravenously or in an insulin infusion pump. • LEVEMIR FlexPen dials in 1-unit increments. • Use the LEVEMIR FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. 2.2 General Dosing Instructions • LEVEMIR can be administered by subcutaneous injection once or twice daily. Administer once daily doses with the evening meal or at bedtime. For twice daily dosing, administer the evening dose with the evening meal, at bedtime, or 12 hours after the morning dose. • Individualize and titrate the dose of LEVEMIR based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal. • Dose adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions ( 5.3 )]. • In patients with type 1 diabetes, LEVEMIR must be used in a regimen with rapid-acting or short-acting insulin. 2.3 Starting Dose in Insulin Naïve Patients Recommended Starting Dosage in Patients with Type 1 Diabetes The recommended starting dose of LEVEMIR in patients with type 1 diabetes mellitus is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be administered as short-acting pre-meal insulin. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose in insulin naïve patients with type 1 diabetes. Recommended Starting Dosage in Patients with Type 2 Diabetes The recommended starting dose of LEVEMIR in patients with type 2 diabetes mellitus inadequately controlled on oral antidiabetic medications or a GLP-1 receptor agonist is 10 units (or 0.1 units/kg to 0.2 units/kg) given once daily in the evening or divided into a twice daily regimen. 2.4 Switching to LEVEMIR from Other Insulin Therapies Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to LEVEMIR from another insulin therapy [see Warnings and Precautions ( 5.3 )]. • If converting from insulin glargine to LEVEMIR, the change can be done on a unit-to-unit basis. • If converting from NPH insulin, the change can be done on a unit-to-unit basis. However, some patients with type 2 diabetes mellitus may require more LEVEMIR than NPH insulin, as observed in one trial [see Clinical Studies ( 14 )] .

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. LEVEMIR is a long-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus ( 1 ). Limitations of Use: Not recommended for the treatment of diabetic ketoacidosis.

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. Lowering the insulin dosage, and adjustments in meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use or 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.

7 DRUG INTERACTIONS Table 6 includes clinically significant drug interactions with LEVEMIR. Table 6: Clinically Significant Drug Interactions with LEVEMIR Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors. Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when LEVEMIR is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of LEVEMIR Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones. Intervention: Dosage increases and increased frequency of glucose monitoring may be required when LEVEMIR is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of LEVEMIR Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dosage adjustment and increased frequency of glucose monitoring may be required when LEVEMIR is co-administered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine Intervention: Increased frequency of glucose monitoring may be required when LEVEMIR is co-administered with these drugs. • Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7 ) • Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The primary activity of insulin, including LEVEMIR, is regulation of glucose metabolism. Insulins and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis. 12.2 Pharmacodynamics Insulin detemir is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak. The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir molecules from the injection site due to self-association of the drug molecules. In addition, the distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin. Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after the subcutaneous injection of LEVEMIR. The mean time between injection and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to >24 hours (24 hours was the end of the observation period). Figure 2: Glucose Lowering Effect in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study 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: Glucose Lowering Effect in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study Figure 2: Graph of glucose lowering effect in patients with type 1 diabetes Figure 3: graph of glucose lowering effect in patients with type 2 diabetes 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 AUC 0-5h was 30-40% lower and AUC 0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions. The absolute bioavailability of insulin detemir is approximately 60%. Distribution Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs. Elimination After subcutaneous administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours depending on dose. Specific Populations Pediatric Patients The pharmacokinetic properties of LEVEMIR were studied in pediatric patients 6-12 years, 13-17 years, and adults with type 1 diabetes. In pediatric patients 6-12 years, the insulin detemir plasma area under the curve (AUC) and C max were increased by 10% and 24%, respectively, as compared to adults. There was no difference in pharmacokinetics between pediatric patients 13-17 years and adults. Geriatrics In a clinical trial studying differences in pharmacokinetics of a single subcutaneous dose of LEVEMIR in young (20 to 35 years) versus elderly (≥68 years) healthy subjects, the insulin detemir AUC was up to 35% higher among the elderly subjects due to reduced clearance [see Use in Specific Populations (8.5)] . Gender No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed between males and females. Race In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of LEVEMIR were studied in a clamp study comparing patients with type 2 diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR were comparable in these three populations. Renal impairment A single subcutaneous dose of 0.2 units/kg of LEVEMIR was administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate, severe, and hemodialysis-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.

12.1 Mechanism of Action The primary activity of insulin, including LEVEMIR, is regulation of glucose metabolism. Insulins and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis.

12.2 Pharmacodynamics Insulin detemir is a soluble, long-acting basal human insulin analog with up to a 24-hour duration of action. The pharmacodynamic profile of LEVEMIR is relatively constant with no pronounced peak. The duration of action of LEVEMIR is mediated by slowed systemic absorption of insulin detemir molecules from the injection site due to self-association of the drug molecules. In addition, the distribution of insulin detemir to peripheral target tissues is slowed because of binding to albumin. Figure 2 shows results from a study in patients with type 1 diabetes conducted for a maximum of 24 hours after the subcutaneous injection of LEVEMIR. The mean time between injection and the end of pharmacological effect for insulin detemir ranged from 7.6 hours to >24 hours (24 hours was the end of the observation period). Figure 2: Glucose Lowering Effect in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study 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: Glucose Lowering Effect in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study Figure 2: Graph of glucose lowering effect in patients with type 1 diabetes Figure 3: graph of glucose lowering effect in patients with type 2 diabetes

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 AUC 0-5h was 30-40% lower and AUC 0-inf was 10% lower than the corresponding AUCs with subcutaneous injections to the deltoid and abdominal regions. The absolute bioavailability of insulin detemir is approximately 60%. Distribution Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg. More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs. Elimination After subcutaneous administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours depending on dose. Specific Populations Pediatric Patients The pharmacokinetic properties of LEVEMIR were studied in pediatric patients 6-12 years, 13-17 years, and adults with type 1 diabetes. In pediatric patients 6-12 years, the insulin detemir plasma area under the curve (AUC) and C max were increased by 10% and 24%, respectively, as compared to adults. There was no difference in pharmacokinetics between pediatric patients 13-17 years and adults. Geriatrics In a clinical trial studying differences in pharmacokinetics of a single subcutaneous dose of LEVEMIR in young (20 to 35 years) versus elderly (≥68 years) healthy subjects, the insulin detemir AUC was up to 35% higher among the elderly subjects due to reduced clearance [see Use in Specific Populations (8.5)] . Gender No clinically relevant differences in pharmacokinetic parameters of LEVEMIR are observed between males and females. Race In two clinical pharmacology studies conducted in healthy Japanese and Caucasian subjects, there were no clinically relevant differences seen in pharmacokinetic parameters. The pharmacokinetics and pharmacodynamics of LEVEMIR were studied in a clamp study comparing patients with type 2 diabetes of Caucasian, African-American, and Latino origin. Dose-response relationships for LEVEMIR were comparable in these three populations. Renal impairment A single subcutaneous dose of 0.2 units/kg of LEVEMIR was administered to healthy subjects and those with varying degrees of renal impairment (mild, moderate, severe, and hemodialysis-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.

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3 DOSAGE FORMS AND STRENGTHS Injection: 100 units/mL (U-100), is a clear, colorless, solution available as: • 3 mL single-patient-use FlexPen prefilled pen • 10 mL multiple-dose vial Injection: 100 units/mL (U-100) of insulin detemir available as: • 3 mL single-patient-use FlexPen ® prefilled pen ( 3 ) • 10 mL multiple-dose vial ( 3 )

Levemir insulin detemir INSULIN DETEMIR INSULIN DETEMIR SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM GLYCERIN METACRESOL PHENOL SODIUM CHLORIDE ZINC WATER HYDROCHLORIC ACID SODIUM HYDROXIDE Levemir insulin detemir INSULIN DETEMIR INSULIN DETEMIR SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM GLYCERIN METACRESOL PHENOL SODIUM CHLORIDE ZINC WATER HYDROCHLORIC ACID SODIUM HYDROXIDE Levemir insulin detemir INSULIN DETEMIR INSULIN DETEMIR SODIUM PHOSPHATE, DIBASIC, UNSPECIFIED FORM GLYCERIN METACRESOL PHENOL SODIUM CHLORIDE ZINC WATER HYDROCHLORIC ACID SODIUM HYDROXIDE

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.

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.

BLA021536

Levemir

insulin detemir

0169-6438

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

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 Use only with a U-100 syringe. 10 mL Multiple-dose Vial novo nordisk ® Image of Levemir vial carton

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for the Vials and LEVEMIR FlexPen Prefilled Pen. Never Share a LEVEMIR FlexPen or Insulin Syringe Between Patients Advise patients that they must never share a LEVEMIR FlexPen with another person, even if the needle is changed. Advise patients using LEVEMIR vials not to share needles or insulin syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions ( 5.1 )]. Hyperglycemia or Hypoglycemia Inform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). This may present a risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions ( 5.3 )] . Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions ( 5.2 )] . Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with LEVEMIR. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.5 )]. Hypoglycemia Due to Medication Errors Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)] . Novo Nordisk ® , Levemir ® , NovoLog ® , FlexPen ® , and NovoFine ® are registered trademarks of Novo Nordisk A/S. Patent Information: https://www.novonordisk-us.com/products/product-patents.html © 2005-2022 Novo Nordisk Manufactured by: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, NJ 08536 U.S. License Number 1261 For information about LEVEMIR contact: Novo Nordisk Inc. 800 Scudders Mill Road Plainsboro, New Jersey 08536 1-800-727-6500 www.novonordisk-us.com

14 CLINICAL STUDIES The efficacy and safety of LEVEMIR given once-daily at bedtime or twice-daily (before breakfast and at bedtime, before breakfast and with the evening meal, or at 12-hour intervals) was compared to that of once-daily or twice-daily NPH insulin in open-label, randomized, parallel trials of 1155 adults with type 1 diabetes mellitus, 347 pediatric patients with type 1 diabetes mellitus, and 869 adults with type 2 diabetes mellitus. The efficacy and safety of LEVEMIR given twice-daily was compared to once-daily insulin glargine in an open-label, randomized, parallel trial of 320 patients with type 1 diabetes. The evening LEVEMIR dose was titrated in all trials according to pre-defined targets for fasting blood glucose. The pre-dinner blood glucose was used to titrate the morning LEVEMIR dose in those trials that also administered LEVEMIR in the morning. In general, the reduction in HbA 1c with LEVEMIR was similar to that with NPH insulin or insulin glargine. 14.1 Clinical Studies in Adult Patients with Type 1 Diabetes In a 16-week open-label clinical trial (Study A, n=409), adults with type 1 diabetes were randomized to treatment with either LEVEMIR at 12-hour intervals, LEVEMIR administered in the morning and bedtime or NPH insulin administered in the morning and bedtime. Insulin aspart was also administered before each meal. At 16 weeks of treatment, the combined LEVEMIR-treated patients had similar HbA 1c and fasting plasma glucose (FPG) reductions compared to the NPH-treated patients (Table 7). Differences in timing of LEVEMIR administration had no effect on HbA 1c , fasting plasma glucose (FPG), or body weight. In a 26-week, open-label clinical trial (Study B, n=320), adults with type 1 diabetes were randomized to twice-daily LEVEMIR (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 HbA 1c similar to that of insulin glargine-treated patients. In a 24-week, open-label clinical trial (Study C, n=749), adults with type 1 diabetes were randomized to once-daily LEVEMIR or once-daily NPH insulin, both administered at bedtime and in combination with regular human insulin before each meal. LEVEMIR and NPH insulin had a similar effect on HbA 1c. Table 7: Type 1 Diabetes Mellitus – Adult Study A Study B Study C Treatment duration 16 weeks 26 weeks 24 weeks Treatment in combination with NovoLog (insulin aspart) NovoLog (insulin aspart) Human Soluble Insulin (regular insulin) Twice-daily LEVEMIR Twice-daily NPH Twice-daily LEVEMIR Once-daily insulin glargine Once-daily LEVEMIR Once-daily NPH Number of patients treated 276 133 161 159 492 257 HbA 1c (%) Baseline HbA 1c 8.6 8.5 8.9 8.8 8.4 8.3 Adj. mean change from baseline -0.8* -0.7* -0.6** -0.5** -0.1* 0.0* LEVEMIR – NPH 95% CI for Treatment difference -0.2 (-0.3, -0.0) -0.0 (-0.2, 0.2) -0.1 (-0.3, 0.0) Fasting blood glucose (mg/dL) Baseline mean 209 220 153 150 213 206 Adj. mean change from baseline -44* -9* -38** -41** -30* -9* *From an ANCOVA model adjusted for baseline value and country. **From an ANCOVA model adjusted for baseline value and study site. 14.2 Clinical Studies in Pediatric Patients with Type 1 Diabetes Two open-label, randomized, controlled clinical trials have been conducted in pediatric patients with type 1 diabetes. One trial (Study D) was 26 weeks in duration and enrolled patients 6 to 17 years of age. The other trial (Study I) was 52 weeks in duration and enrolled patients 2 to 16 years of age. In both trials, LEVEMIR and NPH insulin were administered once- or twice-daily. Bolus insulin aspart was administered before each meal. In the 26-week trial, LEVEMIR-treated patients had a mean decrease in HbA 1c similar to that of NPH insulin (Table 8). In the 52-week trial, the randomization was stratified by age (2-5 years, n=82, and 6-16 years, n=265) and the mean HbA 1c increased in both treatment arms, with similar findings in the 2-5 year-old age group (n=80) and the 6-16 year-old age group (n=258) (Table 8). Table 8: Type 1 Diabetes Mellitus – Pediatric Study D Study I Treatment duration 26 weeks 52 weeks Treatment in combination with NovoLog (insulin aspart) NovoLog (insulin aspart) Once- or Twice Daily LEVEMIR Once- or Twice Daily NPH Once- or Twice Daily LEVEMIR Once- or Twice Daily NPH Number of subjects treated 232 115 177 170 HbA 1c (%) Baseline HbA 1c 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 Clinical Studies in Adult Patients with Type 2 Diabetes In a 24-week, open-label, randomized, clinical trial (Study E, n=476), LEVEMIR administered twice-daily (before breakfast and evening) was compared to NPH insulin administered twice-daily (before breakfast and evening) as part of a regimen of stable combination therapy with one or two of the following oral antidiabetic medications: metformin, an insulin secretagogue, or an alpha–glucosidase inhibitor. All patients were insulin-naïve at the time of randomization. LEVEMIR and NPH insulin similarly lowered HbA 1c from baseline (Table 9). In a 22-week, open-label, randomized, clinical trial (Study F, n=395) in adults with type 2 diabetes, LEVEMIR and NPH insulin were given once- or twice-daily as part of a basal-bolus regimen with insulin aspart. As measured by HbA 1c or FPG, LEVEMIR had efficacy similar to that of NPH insulin. Table 9: Type 2 Diabetes Mellitus – Adult Study E Study F Treatment duration 24 weeks 22 weeks Treatment in combination with oral agents insulin aspart Twice-daily LEVEMIR Twice-daily NPH Once- or Twice Daily LEVEMIR Once- or Twice Daily NPH Number of subjects treated 237 239 195 200 HbA 1c (%) Baseline HbA 1c 8.6 8.5 8.2 8.1 Adj. mean change from baseline -2.0* -2.1* -0.6** -0.6** LEVEMIR – NPH 95% CI for Treatment difference 0.1 (-0.0, 0.3) -0.1 (-0.2, 0.1) Fasting blood glucose 1 (mg/dL) Baseline mean 179 173 - - Adj. mean change from baseline -69* -74* - - 1 Study F - Fasting blood glucose data not collected *From an ANCOVA model adjusted for baseline value, country and oral antidiabetic treatment category. **From an ANCOVA model adjusted for baseline value and country. Combination Therapy with Metformin and Liraglutide This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA 1c 7-10%) on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA 1c 7-8.5%) on metformin (≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with liraglutide titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA 1c <7% with liraglutide 1.8 mg and metformin and continued treatment in a non-randomized, observational arm. Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions. The remaining 323 patients with HbA 1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily LEVEMIR administered in the evening as add-on therapy (n=162) or to continued, unchanged treatment with liraglutide 1.8 mg and metformin (n=161). The starting dose of LEVEMIR was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26-week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with liraglutide 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with LEVEMIR. Treatment with LEVEMIR as add-on to liraglutide 1.8 mg + metformin resulted in statistically significant reductions in HbA 1c and FPG compared to continued, unchanged treatment with liraglutide 1.8 mg + metformin alone (Table 10). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received LEVEMIR add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with liraglutide 1.8 mg + metformin alone. Table 10: Results of a 26-week Open-label Trial of LEVEMIR as Add-on to Liraglutide + Metformin Compared to Continued Treatment with Liraglutide + Metformin Alone in Patients Not Achieving HbA 1c <7% After 12 Weeks of Metformin and Liraglutide Study H LEVEMIR + Liraglutide +Metformin Liraglutide+ Metformin Intent-to-Treat Population (N) a 162 157 HbA 1c (%) (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 A 1c <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) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value *From an ANCOVA model adjusted for baseline value, country and previous oral antidiabetic treatment category. **From a logistic regression model adjusted for baseline HbA 1c. ***p-value <0.0001

8.5 Geriatric Use In clinical trials of LEVEMIR, 64 of 1624 patients (4%) in the type 1 diabetes trials and 309 of 1082 patients (29%) in the type 2 diabetes trials were 65 years or older. A total of 52 (7 type 1 and 45 type 2) patients (2%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but small sample sizes limits conclusions. Greater sensitivity of some older individuals cannot be ruled out. In geriatric patients, the initial dosing, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the geriatric patients.

8.4 Pediatric Use The safety and effectiveness of LEVEMIR to improve glycemic control in pediatric patients with diabetes mellitus have been established. The use of LEVEMIR for this indication is supported by evidence from adequate and well-controlled trials (Studies D and I) in 694 pediatric patients aged 2 to 17 years with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] and from other studies in pediatric patients and adults with diabetes mellitus [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.3 )].

8.1 Pregnancy Risk Summary Available data from published studies and postmarketing case reports with LEVEMIR use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label clinical trial that included 152 pregnant women with type 1 diabetes who were administered LEVEMIR once or twice daily, beginning in gestational weeks 8 to 12 or prior to conception, no clear evidence of maternal or fetal risk associated with LEVEMIR was observed (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were conducted in non-diabetic pregnant rats and rabbits with insulin detemir administration at 3 and 135 times the human dose of 0.5 units/kg/day, respectively, throughout pregnancy. Overall, the effects of insulin detemir did not generally differ from those observed with regular human insulin (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA 1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA 1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic 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 Human Data In an open-label clinical trial, pregnant females with type 1 diabetes (n=310) were treated with LEVEMIR (once or twice daily) or NPH insulin (once, twice, or thrice daily); both groups also received preprandial insulin aspart. Approximately 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. The rates of preeclampsia observed in the study were within expected rates for pregnancy complicated by diabetes. No differences in pregnancy outcomes or the health of the fetus and newborn were seen between the two groups. In this study, the proportion of subjects with severe hypoglycemia and non-severe hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and non-severe hypoglycemia [see Adverse Reactions ( 6.1 )]. In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower level of quantification (<25 pmol/L). Animal Data In a fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose of 0.5 units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day (approximately 135 times a human dose of 0.5 units/kg/day based on AUC ratio) were given to rabbits during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of 900 nmol/kg/day. The rat and rabbit embryo-fetal development studies that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding embryotoxicity and teratogenicity suggesting that the effects seen were the result of hypoglycemia resulting from insulin exposure in normal animals.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published studies and postmarketing case reports with LEVEMIR use in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label clinical trial that included 152 pregnant women with type 1 diabetes who were administered LEVEMIR once or twice daily, beginning in gestational weeks 8 to 12 or prior to conception, no clear evidence of maternal or fetal risk associated with LEVEMIR was observed (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Animal reproduction studies were conducted in non-diabetic pregnant rats and rabbits with insulin detemir administration at 3 and 135 times the human dose of 0.5 units/kg/day, respectively, throughout pregnancy. Overall, the effects of insulin detemir did not generally differ from those observed with regular human insulin (see Data) . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The estimated background risk of major birth defects is 6 to 10% in women with pre-gestational diabetes with a peri-conceptional HbA 1c >7 and has been reported to be as high as 20 to 25% in women with a peri-conceptional HbA 1c >10. The estimated background risk of miscarriage for the indicated population is unknown. Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Hypoglycemia and hyperglycemia occur more frequently during pregnancy in patients with pre-gestational diabetes. Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic 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 Human Data In an open-label clinical trial, pregnant females with type 1 diabetes (n=310) were treated with LEVEMIR (once or twice daily) or NPH insulin (once, twice, or thrice daily); both groups also received preprandial insulin aspart. Approximately 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. The rates of preeclampsia observed in the study were within expected rates for pregnancy complicated by diabetes. No differences in pregnancy outcomes or the health of the fetus and newborn were seen between the two groups. In this study, the proportion of subjects with severe hypoglycemia and non-severe hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and non-severe hypoglycemia [see Adverse Reactions ( 6.1 )]. In about a quarter of infants, LEVEMIR was detected in the infant cord blood at levels above the lower level of quantification (<25 pmol/L). Animal Data In a fertility and embryonic development study, insulin detemir was administered to female rats before mating, during mating, and throughout pregnancy at doses up to 300 nmol/kg/day (3 times a human dose of 0.5 units/kg/day, based on plasma area under the curve (AUC) ratio). Doses of 150 and 300 nmol/kg/day produced numbers of litters with visceral anomalies. Doses up to 900 nmol/kg/day (approximately 135 times a human dose of 0.5 units/kg/day based on AUC ratio) were given to rabbits during organogenesis. Drug and dose related increases in the incidence of fetuses with gallbladder abnormalities such as small, bilobed, bifurcated, and missing gallbladders were observed at a dose of 900 nmol/kg/day. The rat and rabbit embryo-fetal development studies that included concurrent human insulin control groups indicated that insulin detemir and human insulin had similar effects regarding 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 pediatric patients with diabetes mellitus have been established. The use of LEVEMIR for this indication is supported by evidence from adequate and well-controlled trials (Studies D and I) in 694 pediatric patients aged 2 to 17 years with type 1 diabetes mellitus [see Clinical Studies ( 14.2 )] and from other studies in pediatric patients and adults with diabetes mellitus [see Clinical Pharmacology ( 12.3 ), Clinical Studies ( 14.3 )]. 8.5 Geriatric Use In clinical trials of LEVEMIR, 64 of 1624 patients (4%) in the type 1 diabetes trials and 309 of 1082 patients (29%) in the type 2 diabetes trials were 65 years or older. A total of 52 (7 type 1 and 45 type 2) patients (2%) were 75 years or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, but small sample sizes limits conclusions. Greater sensitivity of some older individuals cannot be ruled out. In geriatric patients, the initial dosing, dosage increments, and maintenance dosage should be conservative to avoid hypoglycemia. Hypoglycemia may be difficult to recognize in the geriatric patients. 8.6 Renal Impairment No difference was observed in the pharmacokinetics of LEVEMIR between non-diabetic patients with kidney impairment and healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with kidney impairment. Careful glucose monitoring and dose adjustments of LEVEMIR, may be necessary in patients with kidney impairment [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Non-diabetic patients with severe hepatic impairment had lower systemic exposures to insulin detemir compared to healthy volunteers. However, some studies with human insulin have shown increased circulating insulin concentrations in patients with liver impairment. Careful glucose monitoring and dosage adjustments of LEVEMIR, may be necessary in patients with hepatic impairment [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied LEVEMIR (insulin detemir) injection 100 units/mL (U-100) is a clear and colorless solution available in the following presentations: Presentation NDC 3 mL Single-patient-use FlexPen pen 0169-6432-10 10 mL Multiple-dose vial 0169-3687-12 Additional Information about LEVEMIR FlexPen: • The pen dials in 1-unit increments. • Use NovoFine ® or NovoFine Plus ® disposable needles. • Each pen for use by a single patient. LEVEMIR FlexPen must never be shared between patients, even if the needle is changed. 16.2 Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused (unopened) LEVEMIR in the refrigerator between 36° to 46°F (2° and 8°C). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze. Do not use LEVEMIR if it has been frozen. Keep unused LEVEMIR in the carton so that it stays clean and protected from light. Remove the needle from the LEVEMIR FlexPen pen after each injection and store without a needle attached. Use a new needle for each injection. The storage conditions for vials and LEVEMIR FlexPen prefilled pens are summarized in Table 11: Table 11: Storage Conditions for LEVEMIR FlexPen and Vial LEVEMIR Presentation Not in-use (unopened) In-use (opened) Refrigerated (36°F to 46°F [2°C and 8°C]) Room Temperature (up to 86°F [30°C]) Refrigerated (36°F to 46°F [2°C and 8°C]) Room Temperature (up to 86°F [30°C]) 3 mL single-patient-use LEVEMIR FlexPen Until expiration date 42 days Do not refrigerate 42 days 10 mL multiple-dose vial Until expiration date 42 days 42 days 42 days