Xultophy 100/3.6

1 INDICATIONS AND USAGE XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide and is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use: • XULTOPHY 100/3.6 contains liraglutide. Coadministration with any other product containing liraglutide or another glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended [see Warnings and Precautions ( 5.5 )]. • XULTOPHY 100/3.6 is not recommended for the treatment of diabetic ketoacidosis. • XULTOPHY 100/3.6 has not been studied in combination with prandial insulin. XULTOPHY 100/3.6 is a combination of insulin degludec, a long-acting human insulin analog, and liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use : ( 1 ) • Coadministration with any other product containing liraglutide or another GLP-1 receptor agonist is not recommended. • Not recommended for the treatment of diabetic ketoacidosis. • Has not been studied in combination with prandial insulin.

2 DOSAGE AND ADMINISTRATION • Administer once-daily at same time each day with or without food. ( 2.1 ) • XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection ( 2.1 , 2.2 ); each XULTOPHY 100/3.6 dosage unit contains 1 unit of insulin degludec and 0.036 mg of liraglutide. ( 2.1 ) • Maximum daily dosage is 50 units (50 units of insulin degludec and 1.8 mg of liraglutide). ( 2.1 ) • Recommended starting dosage in patients naïve to basal insulin or GLP-1 receptor agonist is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) injected subcutaneously once-daily. (2.2 ) • Discontinue therapy with liraglutide or basal insulin prior to initiation of XULTOPHY 100/3.6. ( 2.2 ) • Recommended starting dosage in patients currently on basal insulin or GLP-1 receptor agonist is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) injected subcutaneously once-daily. ( 2.2 ) • See Full Prescribing Information for titration recommendations. ( 2.3 ) • Inject XULTOPHY 100/3.6 subcutaneously into the thigh, upper arm, or abdomen. ( 2.5 ) • Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.5 ) • Do not administer intravenously or by an infusion pump. ( 2.5 ) • Do not dilute or mix with any other insulin products or solutions. ( 2.5 ) 2.1 Important Dosage Information • XULTOPHY 100/3.6 is a combination of insulin degludec and liraglutide. • Administer XULTOPHY 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food. • The XULTOPHY 100/3.6 pen delivers doses from 10 to 50 units with each injection. Table 1 presents the units of insulin degludec and the milligrams of liraglutide in each dosage of XULTOPHY 100/3.6 [see Dosage and Administration ( 2.2 )]. • The maximum dosage of XULTOPHY 100/3.6 is 50 units daily (50 units of insulin degludec and 1.8 mg of liraglutide) [see Warnings and Precautions ( 5.5 )] . 2.2 Recommended Starting Dosage In patients naïve to basal insulin or a GLP-1 receptor agonist • The recommended starting dosage of XULTOPHY 100/3.6 is 10 units (10 units of insulin degludec and 0.36 mg of liraglutide) injected subcutaneously once-daily (see Table 1 ). In patients currently on basal insulin or a GLP-1 receptor agonist • Discontinue therapy with basal insulin or GLP-1 receptor agonist prior to initiation of XULTOPHY 100/3.6. • The recommended starting dosage of XULTOPHY 100/3.6 is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) injected subcutaneously once-daily (see Table 1 ). Table 1. Units of Insulin Degludec and Milligrams of Liraglutide in Each Dosage of XULTOPHY 100/3.6 XULTOPHY 100/3.6 (dose counter display) * insulin degludec component dose liraglutide component dose Comment ▪▪ ─ --- --- Priming symbol 10 10 units 0.36 mg Recommended starting dose for patients naïve to basal insulin or GLP-1 receptor agonist 11 11 units 0.4 mg 12 12 units 0.43 mg 13 13 units 0.47 mg 14 14 units 0.5 mg 15 15 units 0.54 mg 16 16 units 0.58 mg Recommended starting dose for patients currently on basal insulin or GLP-1 receptor agonist 17 17 units 0.61 mg 18 18 units 0.65 mg 19 19 units 0.68 mg 20 20 units 0.72 mg 21 21 units 0.76 mg 22 22 units 0.79 mg 23 23 units 0.83 mg 24 24 units 0.86 mg 25 25 units 0.9 mg 26 26 units 0.94 mg 27 27 units 0.97 mg 28 28 units 1.01 mg 29 29 units 1.04 mg 30 30 units 1.08 mg 31 31 units 1.12 mg 32 32 units 1.15 mg 33 33 units 1.19 mg 34 34 units 1.22 mg 35 35 units 1.26 mg 36 36 units 1.3 mg 37 37 units 1.33 mg 38 38 units 1.37 mg 39 39 units 1.4 mg 40 40 units 1.44 mg 41 41 units 1.48 mg 42 42 units 1.51 mg 43 43 units 1.55 mg 44 44 units 1.58 mg 45 45 units 1.62 mg 46 46 units 1.66 mg 47 47 units 1.69 mg 48 48 units 1.73 mg 49 49 units 1.76 mg 50 50 units 1.8 mg Maximum daily dosage [see Warnings and Precautions (5.5)] * The dose counter on the XULTOPHY 100/3.6 pen displays numbers for the even units and displays lines for the odd units. 2.3 Titration of XULTO…

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 ) • Never share a XULTOPHY 100/3.6 pen between patients, even if the needle is changed. ( 5.3 ) • 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. ( 5.4 ) • Overdose due to medication errors : XULTOPHY 100/3.6 contains two drugs. Instruct patients to check label before injection since accidental mix-ups with insulin containing products can occur. Do not exceed the maximum dose or administer with other GLP-1 receptor agonists. ( 5.5 ) • Hypoglycemia: May be life-threatening. Increase monitoring with changes to : dosage, concomitant drugs, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. ( 5.6 ) • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.7 ) • Severe Gastrointestinal Adverse Reactions : Use has been associated with gastrointestinal adverse reactions, sometimes severe. XULTOPHY 100/3.6 is not recommended in patients with severe gastroparesis. ( 5.8 ) • Hypersensitivity Reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, angioedema, bronchospasm, hypotension, and shock can occur. If a hypersensitivity reaction occurs, discontinue and treat per standard of care. ( 5.9 ) • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.10 ) • Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. ( 5.11 ) • Fluid retention and congestive heart failure with use of thiazolidinediones (TZDs) : Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. ( 5.12 ) • Pulmonary Aspiration During General Anesthesia or Deep Sedation : Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.13 ) 5.1 Risk of Thyroid C-cell Tumors Liraglutide, one of the components of XULTOPHY 100/3.6, causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether XULTOPHY 100/3.6 will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. XULTOPHY 100/3.6 is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of XULTOPHY 100/3.6 and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with XULTOPHY 100/3.6. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and…

4 CONTRAINDICATIONS XULTOPHY 100/3.6 is contraindicated: • In patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) [see Warnings and Precautions ( 5.1 )] . • During episodes of hypoglycemia [see Warnings and Precautions ( 5.6 )] . • In patients with hypersensitivity to insulin degludec, liraglutide, or any of the excipients in XULTOPHY 100/3.6. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with liraglutide, one of the components of XULTOPHY 100/3.6 [see Warnings and Precautions ( 5.9 )]. • Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 ( 4 ) • During episodes of hypoglycemia ( 4 ) • Patients with a serious hypersensitivity reaction to insulin degludec, liraglutide, or any of the excipients in XULTOPHY 100/3.6 ( 4 )

7 DRUG INTERACTIONS • Drugs that affect glucose metabolism : Adjustment of XULTOPHY 100/3.6 dosage may be needed; closely monitor blood glucose. ( 7.1 ) • Anti-Adrenergic drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Hypoglycemia signs and symptoms may be reduced or absent. ( 7.1 ) • Effects of delayed gastric emptying on oral medications : May impact absorption of concomitantly administered oral medications. ( 7.2 ) 7.1 Medications that Can Affect Glucose Metabolism A number of medications affect glucose metabolism and may require dose adjustment of XULTOPHY 100/3.6 and particularly close monitoring [see Dosage and Administration ( 2.2 ), Warnings and Precautions ( 5.6 )]. 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 Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6 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 XULTOPHY 100/3.6 is coadministered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of XULTOPHY 100/3.6 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 XULTOPHY 100/3.6 is coadministered 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 XULTOPHY 100/3.6 is coadministered with these drugs. 7.2 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide-containing products, including XULTOPHY 100/3.6, cause a delay of gastric emptying, and thereby have the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree [see Clinical Pharmacology ( 12.3 )] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide containing products.

8.1 Pregnancy Risk Summary Based on animal reproduction studies, there may be risks to the fetus from exposure to liraglutide during pregnancy. XULTOPHY 100/3.6 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There are no available data with XULTOPHY 100/3.6, insulin degludec or liraglutide in pregnant women to inform a drug associated risk for major birth defects and miscarriage. There are clinical considerations regarding the risks of poorly controlled diabetes in pregnancy (see Clinical Considerations). For insulin degludec, rats and rabbits were exposed in animal reproduction studies at 5 times (rat) and 10 times (rabbit) the human exposure at a dose of 0.75 U/kg/day. No adverse outcomes were observed for pregnant animals and offspring (see Data) . For liraglutide, animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD (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 pregestational 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 mellitus increases the fetal risk for major birth defects, stillbirth, macrosomia related morbidity. Data Animal Data Insulin degludec 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 was 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. Liraglutide Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day…

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Hypoglycemia [see Warnings and Precautions ( 5.6 )] • Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.7 )] • Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.8 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.9 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.10 )] • Hypokalemia [see Warnings and Precautions ( 5.11 )] • Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.13 )] • Most common adverse reactions (incidence ≥5%) in clinical trials are nasopharyngitis, headache, nausea, diarrhea, increased lipase and upper respiratory tract infection. ( 6 ) • Immunogenicity-related events, including urticaria, were more common among liraglutide-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. ( 12.6 ) 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 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. XULTOPHY 100/3.6 The data in Table 3 reflect the exposure of 1881 patients to XULTOPHY 100/3.6 and a mean duration of exposure of 33 weeks in trials NCT01336023, NCT01618162, NCT02773368, NCT01676116, NCT01392573, NCT01952145 [see Clinical Studies ( 14.2 and 14.3 )] . The mean age was 57 years and 3% were older than 75 years; 53% were male, 75% were White, 6% were Black or African American and 16% were Hispanic or Latino. The mean body mass index (BMI) was 31.8 kg/m 2 . The mean duration of diabetes was 9 years and the mean HbA 1c at baseline was 8.2%. A history of neuropathy, ophthalmopathy, nephropathy and cardiovascular disease at baseline was reported in 25%, 12%, 7% and 6% respectively. The mean estimated glomerular filtration rate (eGFR) at baseline was 88.3 mL/min/1.73 m 2 and 6% of the patients had an eGFR less than 60 mL/min/1.73 m 2 . Table 3: Adverse Reactions Occurring in ≥5% of XULTOPHY 100/3.6-Treated Patients with Type 2 Diabetes Mellitus XULTOPHY 100/3.6 N = 1881 % Nasopharyngitis 10 Headache 9 Nausea 8 Diarrhea 8 Increased Lipase 7 Upper respiratory tract infection 6 Hypoglycemia Hypoglycemia was the most commonly observed adverse reaction in patients treated with insulin and insulin containing products, including XULTOPHY 100/3.6 [see Warnings and Precautions ( 5.6 )]. The number of reported hypoglycemia episodes depended on the definition of hypoglycemia used, 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 XULTOPHY 100/3.6 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 phase 3 clinical program [see Clinical Studies ( 14 )] , events of severe hypoglycemia were defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions ( Table 4 ). Hypoglycemia episodes with a glucose level below 54 mg/dL associated with or without symptoms is shown in Table 4 . No clinically important differences in risk of severe hypoglycemia between XULTOPHY 100/3.6 and comparators were observed in clinical trials. Table 4. Hypoglycemia Episodes Reported in XULTOPHY 100/3.6-Treated Patients with T2DM † Episode requiring assistance of another person to activel…