INSULIN DEGLUDEC

Insulin degludec is a long-acting basal human insulin analog for subcutaneous injection produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae followed by chemical modification. Insulin degludec differs from human insulin in that the amino acid threonine in position B30 has been omitted and a side-chain consisting of glutamic acid and a C16 fatty acid has been attached (chemical name: LysB29(Nε-hexadecandioyl-γ-Glu) des(B30) human insulin). Insulin degludec has a molecular formula of C 274 H 411 N 65 O 81 S 6 and a molecular weight of 6.104 kDa. It has the following structure: Figure 1: Structural Formula of Insulin Degludec Insulin Degludec injection is a sterile, aqueous, clear, and colorless solution available as 100 units/mL (U-100) or 200 units/mL (U-200) for subcutaneous use. For the 100 units/mL solution, each mL contains 100 units of insulin degludec and glycerin (19.6 mg), metacresol (1.72 mg), phenol (1.5 mg), zinc (32.7 mcg), and Water for Injection, USP. For the 200 units/mL solution, each mL contains 200 units of insulin degludec and glycerin (19.6 mg), metacresol (1.72 mg), phenol (1.5 mg), zinc (71.9 mcg), and Water for Injection, USP. Insulin Degludec has a pH of approximately 7.6. Hydrochloric acid or sodium hydroxide may be added to adjust pH. Figure 1: Structural Formula of Tresiba

Insulin Degludec is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus. Limitations of Use • Not recommended for the treatment of diabetic ketoacidosis. Insulin Degludec is a long-acting human insulin analog indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus ( 1 ). Limitations of Use: • Not recommended for the treatment of diabetic ketoacidosis.

• See Full Prescribing Information for important administration instructions ( 2.1 ). • Inject Insulin Degludec subcutaneously into the thigh, upper arm, or abdomen ( 2.1 ). • Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis ( 2.1 ). • For pediatric patients requiring less than 5 units of Insulin Degludec each day, use an Insulin Degludec U-100 vial ( 2.1 ). • In adults, inject subcutaneously once daily at any time of day ( 2.2 ). • In pediatric patients inject subcutaneously once daily at the same time every day ( 2.2 ). • Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.2 ). • The recommended days between dose increases are 3 to 4 days ( 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. This product is Tresiba (insulin degludec) [see Warnings and Precautions ( 5.4 ) ] . • Inspect visually for particulate matter and discoloration. Only use Insulin Degludec if the solution appears clear and colorless. • Inject Insulin Degludec 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 ( 6.1 , 6.3 )]. • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . • For pediatric patients requiring less than 5 units of Insulin Degludec each day, use the Insulin Degludec U-100 vial. • DO NOT administer Insulin Degludec intravenously or in an insulin infusion pump. • DO NOT dilute or mix Insulin Degludec with any other insulin or solution. • DO NOT transfer Insulin Degludec from the Insulin Degludec FlexTouch pen into a syringe for administration [see Warnings and Precautions ( 5.4 )]. • Use Insulin Degludec FlexTouch pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. 2.2 General Dosing Instructions • Insulin Degludec is available in 2 concentrations (U-100 and U-200): o Insulin Degludec U-100 is available, as a single-patient use FlexTouch pen and multiple-dose vial. ▪ The FlexTouch pen delivers doses in 1 unit increments and can deliver up to 80 units in a single injection. o Insulin Degludec U-200 is available as a single-patient-use FlexTouch pen. ▪ The FlexTouch pen delivers doses in 2 unit increments and can deliver up to 160 units in a single injection. • DO NOT perform dose conversion when using the Insulin Degludec U-100 or U-200 FlexTouch pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. • In adults, inject Insulin Degludec subcutaneously once-daily at any time of day. • In pediatric patients inject Insulin Degludec subcutaneously once-daily at the same time every day. • Individualize and titrate the dose of Insulin Degludec based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal . • The recommended days between dose increases are 3 to 4 days. • 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 )] . • For adult patients, instruct patients who miss a dose of Insulin Degludec to inject their daily dose during waking hours upon discovering the missed dose. Instruct patients to ensure that at least 8 hours have elapsed between consecutive Insulin Degludec injections. • For pediatric patients, instruct patients who miss a dose of Insulin Degludec to contact their healthcare provider for guidance and to monitor blood glucose levels more frequently until the next scheduled Insulin Degludec dose. • In patients with type 1 diabetes, Insulin Degludec must be used concomitantly with short-acting insulin. 2.3 Starting Dose in Insulin Naïve Patients Recommended Starting Dosage in Patients with Type 1 Diabetes Mellitus: The recommended starting dose of Insulin Degludec in insulin naïve patients with type 1 diabetes 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 a short-acting insulin and divided between each daily meal. 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 Mellitus: The recommended starting dose of Insulin Degludec in insulin naïve patients with type 2 diabetes mellitus is 10 units once daily. 2.4 Switching to Insulin Degludec from Other Insulin Therapies Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to Insulin Degludec from another insulin therapy [see Warnings and Precautions ( 5.3 )]. Adults with Type 1 or Type 2 Diabetes Mellitus: Start Insulin Degludec at the same unit dose as the total daily long or intermediate-acting insulin unit dose. Pediatric Patients 1 Year of Age and Older with Type 1 or Type 2 Diabetes Mellitus: Start Insulin Degludec at 80% of the total daily long or intermediate-acting insulin unit dose to minimize the risk of hypoglycemia [see Warnings and Precautions ( 5.2 )].

Insulin Degludec is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . • In patients with hypersensitivity to insulin degludec or any of the excipients in Insulin Degludec [see Warnings and Precautions ( 5.5 )] . • During episodes of hypoglycemia ( 4 ). • Hypersensitivity to insulin degludec or any of the excipients in Insulin Degludec ( 4 ).

The following adverse reactions are also 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 commonly associated with Insulin Degludec are: • hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema and weight gain ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Pharma, 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 conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Insulin Degludec in subjects with type 1 diabetes or type 2 diabetes was evaluated in nine trials of 6-12 month duration in adults and in one trial of 12-month duration in pediatric patients 1 year of age and older with type 1 diabetes. The cardiovascular safety of Insulin Degludec was evaluated in one double-blinded, event-driven trial of 2-year median duration in patients with type 2 diabetes at high risk of cardiovascular events [see Clinical Studies (14)]. The data in Table 1 reflect the exposure of 1102 adults with type 1 diabetes to Insulin Degludec with a mean exposure duration to Insulin Degludec of 34 weeks in three open-label trials; Study A, B and C [see Clinical Studies (14.1)] . The mean age was 43 years and 1% were older than 75 years. Fifty-seven percent were male, 81% were White, 2% were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 26 kg/m 2 . The mean duration of diabetes was 18 years and the mean HbA 1c at baseline was 7.8%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 11%, 16%, 7% and 0.5% respectively. The mean eGFR at baseline was 87 mL/min/1.73 m 2 and 7% of the patients had an eGFR less than 60 mL/min/1.73 m 2 . The data in Table 2 reflect the exposure of 2713 adults with type 2 diabetes to Insulin Degludec with a mean exposure duration to Insulin Degludec of 36 weeks in six open-label trials; Study D, E, F, G, H and I [see Clinical Studies (14.3)] . The mean age was 58 years and 3% were older than 75 years. Fifty-eight percent were male, 71% were White, 7% were Black or African American and 13% were Hispanic. The mean BMI was 30 kg/m 2 . The mean duration of diabetes was 11 years and the mean HbA 1c at baseline was 8.3%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported for 14%, 10%, 6% and 0.6% of participants respectively. At baseline, the mean eGFR was 83 mL/min/1.73 m 2 and 9% had an eGFR less than 60 mL/min/1.73 m 2 . Common adverse reactions (excluding hypoglycemia) occurring in Insulin Degludec treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and adults with type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. Common adverse reactions were defined as reactions occurring in ≥5% of the population studied. Hypoglycemia is not shown in these tables but discussed in a dedicated subsection below. 174 pediatric patients 1 year of age and older with type 1 diabetes were exposed to Insulin Degludec with a mean exposure to Insulin Degludec of 48 weeks. The mean age was 10 years: 25% were ages 1-5 years, 40% were ages 6-11 years, and 35% were ages 12-17 years. 55% were male, 78% were White, 3% were Black or African American and 4% were Hispanic. The mean body mass index (BMI) was 18.7 kg/m 2 . The mean duration of diabetes was 3.9 years and the mean HbA 1c at baseline was 8.2%. Common adverse reactions in Insulin Degludec treated pediatric patients with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1. Table 1: Adverse Reactions Occurring in ≥5% of Insulin Degludec-Treated Adult Patients with Type 1 Diabetes Mellitus Adverse Reaction Insulin Degludec (N=1,102) Nasopharyngitis 23.9 % Upper respiratory tract infection 11.9 % Headache 11.8 % Sinusitis 5.1 % Gastroenteritis 5.1 % Table 2: Adverse Reactions Occurring in ≥5% of Insulin Degludec-Treated Adult Patients with Type 2 Diabetes Mellitus Adverse Reaction Insulin Degludec (N=2,713) Nasopharyngitis 12.9 % Headache 8.8 % Upper respiratory tract infection 8.4 % Diarrhea 6.3 % Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with Insulin Degludec. The rates of reported hypoglycemia depended 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 Insulin Degludec 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. In the open-label adult clinical trials of patients with type 1 and type 2 diabetes, and in the open-label pediatric clinical trial of patients with type 1 diabetes, percentages of adult and pediatric patients with type 1 diabetes randomized to Insulin Degludec who experienced at least one episode of hypoglycemia in clinical trials [see Clinical Studies ( 14 )] and adults with type 2 diabetes are shown in Tables 3 and 4, respectively. Severe hypoglycemia in the open-label trials with adult patients was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Severe hypoglycemia in the pediatric trial was defined as an altered mental status where the child could not assist in his own care, was semiconscious or unconscious, or in a coma ± convulsions and may require parenteral therapy (glucagon or intravenous glucose). A hypoglycemia episode was defined as a severe hypoglycemia episode or an episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms). Table 3: Percent (%) of Type 1 Diabetes Patients Experiencing at Least One Episode of Severe Hypoglycemia or Hypoglycemia § on Insulin Degludec in Open-Label Adult and Pediatric Clinical Trials Study A Adults + insulin aspart 52 weeks Study B Adults + insulin aspart 26 weeks Study C Adults + insulin aspart 26 weeks Study J Pediatrics + insulin aspart 52 weeks Insulin Degludec (N=472) Insulin Degludec (N=301) Insulin Degludec at the same time each day (N=165) Insulin Degludec at alternating times (N=164) Insulin Degludec (N=174) Severe hypoglycemia* Percent of patients 12.3% 10.6% 12.7% 10.4% 17.8% Hypoglycemia § Percent of patients 95.6% 93.0% 99.4% 93.9% 98.3% * Severe hypoglycemia in pediatric patients: an episode with altered mental status, where the child could not assist in his own care, was semiconscious or unconscious, or in a coma ± convulsions and may require parenteral therapy (glucagon or intravenous glucose). § Hypoglycemia : a severe hypoglycemia episode or an episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms). Table 4: Percent (%) of Patients with Type 2 Diabetes Experiencing at Least One Episode of Severe Hypoglycemia or Hypoglycemia § on Insulin Degludec in Open-Label Adult Clinical Trials Study D + 1-2 OADs* insulin naïve 52 weeks Study E + 1-2 OADs* insulin naïve 26 weeks Study F ± 1-3 OADs* insulin naïve 26 weeks Study G T2DM ± 0-3 OADs* 26 weeks Study H T2DM ± 0-2 OADs* + insulin aspart 52 weeks Study I T2DM ± 1-2 OADs* insulin naïve 26 weeks Insulin Degludec (N=766) Insulin Degludec (N=228) Insulin Degludec (N=284) Insulin Degludec (N=226) Insulin Degludec (alternating time) (N=230) Insulin Degludec (N=753) Insulin Degludec (N=226) Severe Hypoglycemia Percent of patients 0.3% 0 0 0.9% 0.4% 4.5% 0.4% Hypoglycemia § Percent of patients 46.5% 28.5% 50% 43.8% 50.9% 80.9% 42.5% *OAD: oral antidiabetic agent, § Hypoglycemia : a severe hypoglycemia episode or an episode where a laboratory or a self-measured glucose calibrated to plasma was less than 56 mg/dL or where a whole blood glucose was less than 50 mg/dL (i.e., with or without the presence of hypoglycemic symptoms). Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock have occurred with insulin, including Insulin Degludec and may be life threatening. Hypersensitivity (manifested with swelling of tongue and lips, diarrhea, nausea, tiredness, and itching) and urticaria were reported in 0.9% of patients treated with Insulin Degludec. Lipodystrophy Long-term use of insulin, including Insulin Degludec, 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 )] . In the clinical program, lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.3% of patients treated with Insulin Degludec. Injection Site Reactions Patients taking Insulin Degludec may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. In the clinical program, injection site reactions occurred in 3.8% of patients treated with Insulin Degludec. Weight Gain Weight gain can occur with insulin therapy, including Insulin Degludec, and has been attributed to the anabolic effects of insulin. In the clinical program after 52 weeks of treatment, patients with type 1 diabetes treated with Insulin Degludec gained an average of 1.8 kg and patients with type 2 diabetes treated with Insulin Degludec gained an average of 3.0 kg. Peripheral Edema Insulin Degludec may cause sodium retention and edema. In the clinical program, peripheral edema occurred in 0.9% of patients with type 1 diabetes mellitus and 3.0% of patients with type 2 diabetes mellitus treated with Insulin Degludec. 6.2 Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to Insulin Degludec with the incidence of antibodies in other studies or to other products may be misleading. In a 52-week trial of adult insulin-experienced type 1 diabetes patients, 68.9% of patients who received Insulin Degludec were positive at baseline for anti-insulin degludec antibodies and 12.3% of the patients developed anti-insulin degludec antibodies at least once during the trial. In a 52-week trial of pediatric insulin-experienced type 1 diabetes patients, 84.1% of patients who received Insulin Degludec were positive at baseline for anti-insulin degludec antibodies and 5.8% of patients developed anti-insulin degludec antibodies at least once during the trial. In a 52-week trial of adult insulin-naïve type 2 diabetes patients, 1.7% of patients who received Insulin Degludec were positive at baseline for anti-insulin degludec antibodies and 6.2% of patients developed anti-insulin degludec antibodies at least once during the trial. In these trials, between 96.7% and 99.7% of patients who were positive for anti-insulin degludec antibodies were also positive for anti-human insulin antibodies. 6.3 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Insulin Degludec. 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. 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.

Table 5 includes clinically significant drug interactions with Insulin Degludec. Table 5: Clinically Significant Drug Interactions with Insulin Degludec 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 Insulin Degludec is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of Insulin Degludec 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 Insulin Degludec is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Degludec 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 Insulin Degludec 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 Insulin Degludec 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 )