Awiqli

1 INDICATIONS AND USAGE Awiqli is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Awiqli is a long-acting human insulin analog indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1 )

2 DOSAGE AND ADMINISTRATION • Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goals. ( 2.1 ) • See Full Prescribing Information for important administration instructions ( 2.2 ) • Inject Awiqli subcutaneously into the thigh, upper arm, or abdomen. ( 2.2 ) • Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.2 ) • See Full Prescribing Information for the recommended starting dosage in insulin naïve patients ( 2.3 ) and recommendations for switching patients from daily basal insulin. ( 2.4 ) • Closely monitor glucose when switching to Awiqli. ( 2.4 ) 2.1 General Dosing Instructions Awiqli FlexTouch is available as a single-patient-use FlexTouch pen. • Inject Awiqli subcutaneously once-weekly on any day of the week on the same day each week. • The Awiqli FlexTouch pen delivers doses in 10 unit increments and can deliver up to 700 units in a single injection. • Individualize and titrate the dose of Awiqli based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal. • The potency of insulin analogues, including insulin icodec-abae is expressed in units. One (1) unit of insulin icodec-abae corresponds to 1 international unit of human insulin. • Dose adjustments may be needed with changes in renal or hepatic function or during illness to minimize the risk of hypoglycemia or hyperglycemia. Due to the long half-life of Awiqli, adjustment of dose is not advised during acute illness nor if patients make short-term changes in their physical activity level or usual diet. In these situations, consider other applicable adjustments, e.g. glucose intake or changes to other glucose lowering medication [see Warnings and Precautions ( 5.2 , 5.3 )] . 2.2 Important Administration Instructions • Always check the product label before administration [see Warnings and Precautions ( 5.1 )] . • Inspect visually for particulate matter and discoloration. Only use Awiqli if the solution appears clear and colorless. • Inject Awiqli 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 ( 5.3 ), Adverse Reactions ( 6.1 )] . • During changes to a patient’s insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 , 5.3 )] . • Use Awiqli FlexTouch pen with caution in patients with visual impairment that may rely on audible clicks to dial their dose. • DO NOT administer Awiqli intramuscularly, intravenously or in an insulin infusion pump. • DO NOT dilute or mix Awiqli with any other insulin or solution. • DO NOT transfer Awiqli from the Awiqli FlexTouch pen into a syringe for administration [see Warnings and Precautions ( 5.1 )] . 2.3 Recommended Dosage in Insulin Naive Patients The recommended weekly starting dose of Awiqli in insulin naïve patients is 70 units administered subcutaneously once-weekly on the same day each week. 2.4 Switching to Awiqli from Daily Basal Insulin Therapy • Administer the first dose of Awiqli on the day after the last dose of daily basal insulin. • Week 1 dosage : The recommended one-time starting dosage of Awiqli FlexTouch is 1.5 times the total daily basal dosage multiplied by 7 rounded to the nearest 10 units. • Week 2 dosage : The recommended dosage is the previous total daily basal insulin dose multiplied by 7 and then rounded to the nearest 10 units. • See Table 1 for examples of Awiqli dosage for Week 1 and 2, when switching from daily basal insulin therapy. • Week 3 dosage and beyond : The recommended dosage of Awiqli can be titrated from the previous dosage based on the patient’s metabolic needs, blood glucose monitoring results, and glycemic control goal. • When switching fr…

5 WARNINGS AND PRECAUTIONS • Hypoglycemia Due to Medication Errors and Accidental Overdose : Accidental mix-ups between insulin products can occur. Advise patients to always check the product label before each injection to confirm they are using Awiqli and not another insulin or injectable antidiabetic medicine. DO NOT transfer Awiqli from the Awiqli FlexTouch pen into a syringe for administration as overdosage and severe hypoglycemia can result. ( 5.1 ) • Hypoglycemia : May be life-threatening. Increase monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity, and in patients with renal impairment, hepatic impairment or hypoglycemia unawareness. ( 5.2 ) • 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. ( 5.3 ) • Hypersensitivity Reactions : Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Awiqli FlexTouch, monitor and treat if indicated. ( 5.4 ) • Hypokalemia : May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. ( 5.5 ) • Never share an Awiqli FlexTouch pen between patients, even if the needle is changed. ( 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 Hypoglycemia Due to Medication Errors and Accidental Overdose Serious hypoglycemia requiring hospitalization has occurred due to accidental mix-ups between Awiqli and other insulin products or once-weekly injectable antidiabetic medicines, incorrect dose selection, and dosing frequency errors. To avoid dosing errors when switching from daily basal insulin to Awiqli, follow the dosage recommendations in the Dosage and Administration Section ( 2.2 ) . Administer Awiqli once weekly only. Advise patients to always check the product label before each injection to confirm they are using Awiqli and not another insulin or injectable antidiabetic medicine. Prior to initiation, train patients and their caregiver(s) on how to select their weekly Awiqli dosage. Advise patients using other injectable medications for glycemic control that the dosage selection of Awiqli differs [see Dosage and Administration ( 2.2 , 2.3 , 2.4 ), Instructions for Use] . Instruct patients to visually verify the dialed units on the dose counter of the Awiqli FlexTouch prefilled pen before each injection to avoid dosing errors. Do not dial the maximum single dose (700 units) of Awiqli unless this is the prescribed dose [see Dosage and Administration ( 2.4 )] . Do not use a syringe to remove Awiqli from the Awiqli FlexTouch disposable insulin prefilled pen. Monitor patients for signs and symptoms of hypoglycemia, particularly during the first several weeks after initiation or dose escalation of Awiqli. Ensure patients understand how to recognize and manage hypoglycemia [see Warnings and Precautions ( 5.2 )] . 5.2 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulin, including Awiqli [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 an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). Awiqli, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications ( 4 )] . Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding…

4 CONTRAINDICATIONS Awiqli is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.2 )] . • In patients with hypersensitivity to insulin icodec-abae or any of the excipients in Awiqli FlexTouch. Serious hypersensitivity reactions have included anaphylaxis [see Warnings and Precautions ( 5.4 )] . • During episodes of hypoglycemia ( 4 ) • Hypersensitivity to insulin icodec-abae or any of the excipients in Awiqli ( 4 )

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with Awiqli. Table 3: Clinically Significant Drug Interactions with Awiqli Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, sodium-glucose co-transporter 2 (SGLT-2) inhibitors. Intervention: Dose reductions and increased frequency of glucose monitoring may be required when Awiqli is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of Awiqli 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: Dose increases and increased frequency of glucose monitoring may be required when Awiqli is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Awiqli Drugs: Alcohol, beta-blockers, clonidine, and lithium salts.Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when Awiqli 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 Awiqli is co-administered with these drugs. • Drugs that may increase the risk of hypoglycemia : antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. ( 7 ) • Drugs that may decrease the blood glucose lowering effect : atypical antipsychotics, 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. ( 7 ) • Drugs that may increase or decrease the blood glucose lowering effect : Alcohol, beta-blockers, clonidine, lithium salts, and pentamidine. ( 7 ) • Drugs that may blunt the signs and symptoms of hypoglycemia : beta-blockers, clonidine, guanethidine, and reserpine. ( 7 )

8.1 Pregnancy Risk Summary There are no available data with Awiqli in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. 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 icodec-abae in animal reproduction studies during organogenesis. No adverse developmental effects were observed in rats or rabbits at exposures approximately equal to human exposure at a dose of 230 U/week [see Data] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA 1c >7 and has been reported to be as high as 20-25% in women with an HbA 1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated Maternal and/or Embryo/fetal Risk 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 Animal Data Insulin icodec-abae was investigated in studies covering the periods of embryo-fetal development and pre- and post-natal development in rats and the period of embryo-fetal development in rabbits. In these studies, insulin icodec-abae did not cause adverse effects on embryo-fetal development when given subcutaneously at up to 10 U/kg/day in rats and 3 U/kg/day in rabbits, resulting in exposures comparable to human exposure (AUC) at a human subcutaneous dose of 230 U/week. Maternal deaths and abortions were observed in rabbits at human exposures secondary to maternal hypoglycemia. In a pre- and postnatal developmental study in rats where insulin icodec-abae was given by the subcutaneous route at doses up to 8.3 U/kg/day (from Gestation Day 6 through Lactation Day 20), maternal and pup mortality occurred during the lactation period at exposures approximately equal to human exposures, which were secondary to maternal hypoglycemia.

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere: • Hypoglycemia Due to Medication Errors and Accidental Overdose [see Warnings and Precautions ( 5.1 )] • Hypoglycemia [see Warnings and Precautions ( 5.2 )] • Hypersensitivity reactions [see Warnings and Precautions ( 5.4 )] • Hypokalemia [see Warnings and Precautions ( 5.5 )] Adverse reactions commonly associated with Awiqli are: • hypoglycemia, hypersensitivity reactions (e.g., urticaria, swelling face and lips), injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk at 1-844-668-6463 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 Awiqli in patients with type 2 diabetes was evaluated in five clinical trials involving 1,880 adults with type 2 diabetes exposed to Awiqli, with a mean exposure duration of 26 to 52 weeks across the five trials [see Clinical Studies ( 14 )] . The type 2 diabetes population had the following characteristics: mean age was 59 years and 5% were older than 75 years, 59% were male, 71% were White, 3.6% were Black or African American, and 13% were Hispanic or Latino ethnicity. The mean BMI was 30.7 kg/m 2 . The mean duration of diabetes was 13 years and the mean HbA 1c at baseline was 8.6%. At baseline, the mean eGFR was 86.1 mL/min/1.73 m 2 and 11% of patients had an eGFR less than 60 mL/min/1.73 m 2 . Common Adverse Reactions Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients treated with Awiqli [see Warnings and Precautions ( 5.2 )] . 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 Awiqli 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 clinical trials [see Clinical Studies ( 14 )] , events of severe hypoglycemia (level 3) were defined as an episode associated with severe cognitive impairment requiring external assistance for recovery. Hypoglycemia episodes with a glucose level below 54 mg/dL with or without associated symptoms (level 2 hypoglycemia) were also assessed in patients with type 2 diabetes. In the clinical trials of patients with type 2 diabetes, percentages of adults randomized to Awiqli who experienced at least one episode of severe or clinically significant (level 2) hypoglycemia in clinical trials are shown in Table 2 . Table 2: Proportion (%) of Patients with Type 2 Diabetes Experiencing at Least One Episode of Severe (Level 3) or Clinically Significant (Level 2) Hypoglycemia in Clinical Trials Type 2 Diabetes Trial A Trial B Trial C Trial D Trial E c Awiqli + anti-diabetic drugs d insulin naïve 52 weeks (N=492) Awiqli + anti-diabetic drugs e insulin naïve 26 weeks (N=293) Awiqli + anti-diabetic drugs d 26 weeks (N=262) Awiqli ± anti-diabetic drugs d + insulin aspart 26 weeks (N=291) Awiqli + anti-diabetic drugs d insulin naïve 52 weeks (N=542) Level 3 Hypoglycemia a 0.2 0 0 1.4 0 Level 2 Hypoglycemia b 9.8 8.9 14.1 50.9 11.8 a Level 3 hypoglycemia is an episode associated with severe cognitive impairment requiring external assistance for recovery. b Level 2 hypoglycemia is hypoglycemia episode with a self-measured blood glucose level below 54 mg/dL with or without associated symptoms. c In Trial E, Awiqli arm titration was performed via a digital titration app. d Excludes sulfonylureas and glinides. e Sulfonulurea and…