Insulin Degludec

1 INDICATIONS AND USAGE 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.

2 DOSAGE AND ADMINISTRATION • 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 Insuli…

5 WARNINGS AND PRECAUTIONS • Never share an Insulin Degludec FlexTouch pen, insulin syringe, or needle between patients, even if the needle is changed ( 5.1 ). • Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to a patient’s insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring ( 5.2 ). • Hypoglycemia : May be life-threatening. Increase monitoring with changes to: insulin dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness ( 5.3 , 5.4 , 6.1 ). • Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. DO NOT transfer Insulin Degludec from the Insulin Degludec pen into a syringe for administration as overdosage and severe hypoglycemia can result ( 5.4 ). • Hypersensitivity reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Insulin Degludec, monitor and treat if indicated ( 5.5 ). • Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated ( 5.6 ). • Fluid retention and heart failure with concomitant use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs ( 5.7 ). 5.1 Never Share an Insulin Degludec FlexTouch Pen, Needle, or Insulin Syringe Between Patients Insulin Degludec FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Patients using Insulin Degludec vials should never share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions ( 5.3 )] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions ( 6.1 , 6.3 )] . Make any changes to a patient’s insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type 2 diabetes, adjustments in concomitant anti-diabetic treatment may be needed [see Dosage and Administration ( 2.4 )] . 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulin, including Insulin Degludec [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Insulin Degludec, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications ( 4 )]. Hypoglycemia can happen suddenly and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )], or who experience recurrent hypoglycemia. The long-acting effect of Insulin Degludec may delay recovery from h…

4 CONTRAINDICATIONS 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 ).

7 DRUG INTERACTIONS 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 )

8.1 Pregnancy Risk Summary Available data from one unpublished trial and the published literature with Insulin Degludec use during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. In a randomized, parallel-group, open-label actively controlled clinical trial that included 91 pregnant women with type 1 diabetes who were administered Insulin Degludec once daily and insulin aspart, beginning in gestational weeks 8 to 13 or prior to conception, no clear evidence of maternal or fetal risk associated with Insulin Degludec use was observed ( see Data ). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Rats and rabbits were exposed to insulin degludec in animal reproduction studies during organogenesis. Pre-and post-implantation losses and visceral/skeletal abnormalities were observed in rats at doses 5 times (rat) and at 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day. These effects were similar to those observed in rats administered human insulin (NPH) (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, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Data Human Data In an open-label clinical trial, 185 pregnant females with type 1 diabetes were treated with either Insulin Degludec (once daily) or insulin detemir (once or twice daily); both groups received insulin aspart 2 to 4 times daily with meals. There were no significant drug-associated differences in pregnancy outcomes or the health of the fetus and newborn between the two groups. In this study, the proportion of subjects with severe hypoglycemia and hypoglycemia was similar between the two treatment arms; for the definitions of severe hypoglycemia and hypoglycemia [see Adverse Reactions (6.1)]. Poor glucose control during pregnancy in both groups and small sample size were limitations of the study. In about two thirds of infants, insulin degludec was detected in the infant cord blood at levels above the lower level of quantification of the assay. Animal Data Insulin degludec was investigated in studies covering fertility, embryo-fetal development and pre- and post-natal development in rats and during the period of embryo-fetal development in rabbits. Human insulin (NPH insulin) was included as comparator. In these studies, insulin degludec caused pre- and post-implantation losses and visceral/skeletal abnormalities when given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. Overall, the effects of insulin degludec were similar to those observed with human insulin, which were probably secondary to maternal hypoglycemia.

6 ADVERSE REACTIONS 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 …