Insulin Detemir

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.

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 )] .

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.

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.