Insulin Icodec

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 )

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 from daily basal insulin to once-weekly Awiqli close glucose monitoring is recommended. Doses and timing of concurrent rapid-acting or short-acting insulin products or other concomitant antidiabetic treatment may need to be adjusted [see Warnings and Precautions ( 5.1 )] . Table 1. Example Awiqli Weekly Dosages When Switching from Daily Basal Insulin Therapy Previous total daily dosage of basal insulin (units) Week 1 Dosage of Awiqli (units) a Week 2 Dosage of Awiqli (units) b 10 110 70 11 120 80 12 130 80 13 140 90 14 150 100 15 160 110 16 170 110 17 180 120 18 190 130 19 200 130 20 210 140 21 220 150 22 230 150 23 240 160 24 250 170 25 260 180 26 270 180 27 280 190 28 290 200 29 300 200 30 320 210 31 330 220 32 340 220 33 350 230 34 360 240 35 370 250 36 380 250 37 390 260 38 400 270 39 410 270 40 420 280 41 430 290 42 440 290 43 450 300 44 460 310 45 470 320 46 480 320 47 490 330 48 500 340 49 510 340 50 530 350 100 1,050 c 700 a Week 1 dose only: Multiply the previous total daily basal insulin dosage by 7, then multiply by 1.5, and round to the nearest 10 units. b Week 2 dose: Previous total daily basal insulin dosage multiplied by 7, then rounded to the nearest 10 units. c When the required dose is larger than 700 units, split the dose into two injections (e.g., a 1,050 unit dose could be administered as a 700 unit injection followed by a 350 unit injection) 2.5 Recommendations Regarding Missed Doses • If a dose is missed, administer the missed dose as soon as possible within 4 days. Resume the once-weekly dosing schedule, one week from the day the missed dose was administered. • If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. • Increase blood glucose monitoring with missed doses.

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 diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions ( 7 )] , or in patients who experience recurrent hypoglycemia. The long-acting effect of Awiqli may delay recovery from hypoglycemia compared to shorter-acting insulins. Risk Factors for Hypoglycemia The risk of hypoglycemia generally increases with intensity of glycemic control. The risk of hypoglycemia after an injection is related to the duration of action of the insulin [see Clinical Pharmacology ( 12.2 )] and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect over time of Awiqli may vary among different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions ( 7 )] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations ( 8.6 , 8.7 )] . Risk Mitigation Strategies for Hypoglycemia Educate patients and caregivers to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. 5.3 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 ( 5.2 )] 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 )] . 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. Adjustments in concomitant anti-diabetic treatment may be needed [see Dosage and Administration ( 2.4 )] . 5.4 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including Awiqli. If hypersensitivity reactions occur, discontinue Awiqli; treat per standard of care and monitor until symptoms and signs resolve. Awiqli is contraindicated in patients who have had hypersensitivity reactions to insulin icodec-abae or any of the excipients [see Contraindications ( 4 )] . 5.5 Hypokalemia All insulins, including Awiqli, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). 5.6 Never Share an Awiqli FlexTouch Pen or Needle Between Patients Awiqli FlexTouch disposable prefilled pens should never be shared between patients, even if the needle is changed. Sharing poses a risk for transmission of blood-borne pathogens. 5.7 Fluid Retention and Congestive Heart Failure with Concomitant Use of a PPAR Gamma Agonist Thiazolidinediones (TZDs), which are pe

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 )

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 )

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 glinide dosage decreased by 50% at the discretion of the investigator. 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. Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Awiqli and may be life threatening. Hypersensitivity (manifested with urticaria, swelling of face and lips swelling) were reported in 0.4% of patients treated with Awiqli. In the three clinical trials in type 2 patients with antibody samples collected (Trial B, C, and D), hypersensitivity reactions occurred in 0.6% of Awiqli-treated patients with anti-insulin icodec-abae antibodies and in 0.4% of Awiqli-treated patients who did not develop anti-insulin icodec-abae antibodies [see Clinical Pharmacology ( 12.6 )] . Lipodystrophy Long-term use of insulin, including Awiqli, 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 ( 2.2 )] . In clinical trials, lipodystrophy, lipohypertrophy, or lipoatrophy was reported in 0.0% of patients treated with Awiqli. Injection Site Reactions Patients taking Awiqli may experience injection site reactions, including pruritus, bruising, erythema, pain, injection site hypersensitivity, swelling, urticaria and injection site mass. In the clinical trials, injection site reactions occurred in 1.8% of patients treated with Awiqli. In the three clinical trials in type 2 patients with antibody samples collected (Trial B, C, and D), injection site reactions occurred in 2.3% of Awiqli-treated patients with anti-insulin icodec-abae antibodies and in 2.4% of Awiqli-treated patients who did not develop anti-insulin icodec-abae antibodies [see Clinical Pharmacology ( 12.6 )] . Weight Gain Weight gain can occur with insulin therapy, including Awiqli, and has been attributed to the anabolic effects of insulin. In the clinical trials after 26 to 52 weeks of treatment, patients with type 2 diabetes treated with Awiqli gained an average weight of 1.4 to 2.8 kg. Peripheral Edema Awiqli, may cause sodium retention and edema. In the clinical trials, peripheral edema occurred in 1.2% of patients with type 2 diabetes mellitus treated with Awiqli.

Mechanism of Action The primary activity of insulin, including Awiqli, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin also inhibits lipolysis and proteolysis, and enhances protein synthesis. Awiqli binds reversibly to albumin, resulting in a depot in the circulation from which insulin icodec-abae is slowly released. The insulin receptor is activated by insulin icodec-abae leading to a stable glucose-lowering effect over the entire dosing interval of one week. When insulin icodec-abae binds to the human insulin receptor it results in the same pharmacological effects as human insulin.