Fiasp

1 INDICATIONS AND USAGE FIASP is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. • FIASP is a rapid-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus ( 1 ).

2 DOSAGE AND ADMINISTRATION • Individualize and adjust the dosage of FIASP based on route of administration, individual’s metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.3 ). • Dosage adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns, changes in renal or hepatic function or during acute illness ( 2.3 ). • Subcutaneous injection ( 2.2 ): o Inject at the start of a meal or within 20 minutes after starting a meal into the abdomen, upper arm, or thigh. o Rotate injection sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. o Should generally be used in regimens with an intermediate- or long-acting insulin. • Continuous Subcutaneous Infusion (Insulin Pump) ( 2.2 ): o Refer to the insulin infusion pump user manual to see if FIASP can be used. Use in accordance with the insulin pumps’ instructions for use. o Administer by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. • Intravenous Infusion: Administer only under medical supervision after diluting to concentrations from 0.5 to 1 unit/mL insulin aspart in infusion systems using polypropylene infusion bags ( 2.2 ). 2.1 Important Preparation and Administration Instructions • Always check insulin label before administration [see Warnings and Precautions ( 5.4 ) ] . • Inspect FIASP visually before use. It should appear clear and colorless. Do not use FIASP if particulate matter or coloration is seen. • Use FIASP FlexTouch pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. • Use PenFill cartridges with caution in patients with visual impairment. • Do not mix FIASP with any other insulin. 2.2 Route of Administration Instructions Subcutaneous Injection: • Inject FIASP at the start of a meal or within 20 minutes after starting a meal subcutaneously into the abdomen, upper arm, or thigh. • 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 Adverse Reactions ( 6.1 , 6.2 )]. • FIASP given by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin. • Instruct patients on basal-bolus treatment who forget a mealtime dose to monitor their blood glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal. • The FIASP FlexTouch pen dials in 1 unit increments. Continuous Subcutaneous Infusion (Insulin Pump): • Refer to the continuous subcutaneous insulin infusion pump user manual to see if FIASP or FIASP PumpCart can be used with the insulin pump. Use FIASP and FIASP PumpCart in accordance with the insulin pump system’s instructions for use. • Administer FIASP by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not infuse into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) Adverse Reactions ( 6.1 )]. • Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions ( 5.8 )]. • Change FIASP in the pump reservoir at least every 6 days or replace the PumpCart cartridge at least every 4 days, or according to the pump user manual, whichever is shorter. Follow the FIASP-specific information for in-use time because FIASP-specific informa …

3 DOSAGE FORMS AND STRENGTHS Injection: 100 units of insulin aspart per mL (U-100) is available as a clear and colorless solution in: • 10 mL multiple-dose vial • 3 mL single-patient-use FIASP FlexTouch pen • 3 mL single-patient-use PenFill cartridges for use in a PenFill cartridge delivery device • 1.6 mL single-patient-use PumpCart cartridges for use in a compatible insulin pump. Injection: 100 units/mL (U-100) available as: • 10 mL multiple-dose vial ( 3 ) • 3 mL single-patient-use FIASP FlexTouch ® pen ( 3 ) • 3 mL single-patient-use PenFill ® cartridges for use in a PenFill cartridge device ( 3 ) • 1.6 mL single-patient-use PumpCart ® cartridges for use in a compatible insulin pump ( 3 )

4 CONTRAINDICATIONS FIASP is contraindicated: • During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . • In patients with known hypersensitivity to insulin aspart or any of the excipients in FIASP [see Warnings and Precautions ( 5.6 )] . • During episodes of hypoglycemia ( 4 ). • Hypersensitivity to insulin aspart or any of the excipients in FIASP ( 4 ).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen [see Warnings and Precautions ( 5.2 )] • Hypoglycemia [see Warnings and Precautions ( 5.3 )] • Hypokalemia [see Warnings and Precautions ( 5.5 )] • Hypersensitivity and allergic reactions [see Warnings and Precautions ( 5.6 )] Adverse reactions observed with FIASP include: hypoglycemia, allergic reactions, hypersensitivity, injection/infusion site reactions, lipodystrophy, and weight gain ( 6.1 ). 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 actually observed in clinical practice. The data in Table 1 reflect the exposure of 763 adult patients with type 1 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 25 weeks [see Clinical Studies ( 14.2 )] . The mean age was 44.4 years and the mean duration of diabetes was 19.9 years. 59% were male, 93% were White, and 2% were Black or African American; and 7% were Hispanic or Latino. The mean BMI was 26.7 kg/m 2 and the mean HbA 1c at baseline was 7.6%. The data in Table 2 reflect the exposure of 341 adult patients with type 2 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 24 weeks [see Clinical Studies ( 14 )] . The mean age was 59.6 years and the mean duration of diabetes was 13.2 years. 47% were male, 80% were White, and 6% were Black or African American; and 8% were Hispanic or Latino. The mean BMI was 31.5 kg/m 2 and the mean HbA 1c at baseline was 8.0%. The data in Table 3 reflect the exposure of 519 pediatric patients with type 1 diabetes mellitus to FIASP in one clinical trial with a mean exposure duration of 26 weeks [see Clinical Studies ( 14.3 )] . The mean age was 11.7 years and the mean duration of diabetes mellitus was 4.4 years. 54% were male, 81% were White, 16% were Asian and 2% were Black or African American. The mean BMI was 19.7 kg/m 2 and the mean HbA 1c at baseline was 7.6%. Common adverse reactions, excluding hypoglycemia, were defined as events occurring in ≥5% and occurring at the same rate or greater for FIASP-treated patients than comparator-treated patients. Table 1. Adverse Reactions (%*) in Adult Patients with Type 1 Diabetes Mellitus Mealtime FIASP + Insulin detemir (N=386) Postmeal FIASP + Insulin detemir (N=377) Nasopharyngitis 20.2 23.9 Upper respiratory tract infection 9.1 7.4 Nausea 4.9 5.0 Diarrhea 5.4 3.2 Back pain 5.2 4.0 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Table 2. Adverse Reactions (%*) in Adult Patients with Type 2 Diabetes Mellitus FIASP + Insulin glargine (N=341) Urinary tract infection 5.9 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Table 3: Adverse Reactions (%*) in Pediatric Patients with Type 1 Diabetes Mellitus Mealtime FIASP + Insulin degludec (N=261) Postmeal FIASP + Insulin degludec (N=258) Viral upper respiratory tract infection Upper respiratory tract infection Influenza Rhinitis Headache Pyrexia Vomiting 23.0 8.4 7.7 3.8 6.1 8.4 3.4 20.5 12.4 5.8 6.2 10.1 6.2 8.1 *Incidence ≥ 5% and occurring at the same rate or greater with FIASP than comparator Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including FIASP. 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 FIASP with …

7 DRUG INTERACTIONS Table 5 includes clinically significant drug interactions with FIASP. Table 5. Clinically Significant Drug Interactions with FIASP 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: Dose reductions and increased frequency of glucose monitoring may be required when FIASP is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of FIASP 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 FIASP is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of FIASP 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 FIASP 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 FIASP is co-administered with these drugs. • Drugs that Increase Hypoglycemia Risk or Increase or Decrease Blood Glucose Lowering Effect: Adjustment of dosage may be needed; closely monitor blood glucose ( 7 ). • Drugs that Blunt Hypoglycemia Signs and Symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine) : Increased frequency of glucose monitoring may be required ( 7 ).

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data with FIASP in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects or adverse maternal or fetal outcomes [see Data] . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations] . In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8- times and equal to the human subcutaneous dose of 1.0 unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin [see Data] . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA 1c >7% and has been reported to be as high as 20-25% in women with a 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, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. Data Human Data Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart starting during the late 2 nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials. Animal Data Fertility, embryo-fetal and pre-and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of 1.0 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1.0 unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1.0 unit/kg/day for rats and equal to the human subcutaneous dose of 1.0 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia. 8.2 Lactation Risk Summary There are no data on the presence of FIASP in human milk, …

12.1 Mechanism of Action The primary activity of FIASP is the regulation of glucose metabolism. Insulins, including insulin aspart, the active ingredient in FIASP, exert their specific action through binding to insulin receptors. Receptor-bound insulin lowers blood glucose by facilitating cellular uptake of glucose into skeletal muscle and adipose tissue and by inhibiting the output of glucose from the liver. Insulin inhibits lipolysis in the adipocyte, inhibits proteolysis, and enhances protein synthesis.

11 DESCRIPTION Insulin aspart is a rapid-acting insulin analog for subcutaneous or intravenous administration. Insulin aspart is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae . Insulin aspart has the empirical formula C 256 H 381 N 65 0 79 S 6 and a molecular weight of 5825.8 daltons. FIASP (insulin aspart) injection is an aqueous, sterile, clear and colorless solution. Each mL contains 100 units of insulin aspart and the inactive ingredients: arginine (as L-arginine hydrochloride), USP (3.48 mg); dibasic sodium phosphate, USP (0.42 mg); glycerin, USP (3.3 mg); metacresol, USP (1.72 mg); niacinamide, USP (20.8 mg); phenol, USP (1.50 mg); zinc (as zinc acetate), USP (19.6 mcg) and Water for Injection. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH to 7.1. Figure 1

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.5 )] . Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure or neurologic impairment may be treated with an intramuscular/subcutaneous glucagon product for emergency use or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied FIASP (insulin aspart) injection 100 units of insulin aspart per mL (U-100) is available as a clear and colorless solution in the following presentations and packaging configurations: Carton of one 10 mL multiple-dose vials NDC 0169-3201-11 Carton of five 3 mL single-patient-use FIASP FlexTouch pens NDC 0169-3204-15 Carton of five 3 mL single-patient-use PenFill cartridges * NDC 0169-3205-15 Carton of five 1.6 mL single-patient-use PumpCart cartridges** NDC 0169-3206-15 The FIASP FlexTouch pen dials in 1 unit increments. * FIASP PenFill cartridges are designed for use with Novo Nordisk insulin delivery devices. ** FIASP PumpCart cartridges are designed for use in compatible pumps only. 16.2 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Unused FIASP vials should be stored between 2° to 8°C (36° to 46°F) in a refrigerator, but not in or near a freezing compartment. FIASP should not be exposed to excessive heat or light and must never be frozen. Do not use FIASP if it has been frozen. FIASP should not be drawn into a syringe and stored for later use. Keep the cap on the pen in order to protect from light. Remove the needle from the FIASP FlexTouch pen after each injection and store without a needle attached. Use a new needle for each injection. Keep unused vials, FIASP FlexTouch, PenFill Cartridges and PumpCart cartridges in the carton so they will stay clean and protected from light. The storage conditions for vials, FIASP FlexTouch pens, 3 mL PenFill cartridges and 1.6 mL PumpCart cartridges are summarized in Table 12: Table 12. Storage Conditions for Vial, FIASP FlexTouch, PenFill Cartridges and PumpCart Cartridges FIASP presentation Not in-use (unopened) In-use (opened) Room Temperature (up to 30°C [86°F]) Refrigerated (2°C to 8°C [36°F to 46°F]) Room Temperature (up to 30°C [86°F]) Refrigerated (2°C to 8°C [36°F to 46°F]) 10 mL multiple-dose vial 28 days Until expiration date 28 days* (up to 30°C [86°F]) 28 days* 3 mL single-patient-use FIASP FlexTouch pen 28 days Until expiration date 28 days (up to 30°C [86°F]) 28 days 3 mL single-patient-use PenFill cartridges 28 days Until expiration date 28 days (up to 30°C [86°F]) Do not refrigerate 1.6 mL single-patient-use PumpCart cartridges 18 days** Until expiration date 4 days** (up to 37°C [98.6°F]) Do not refrigerate *Pump Reservoir: The total in use time is 28 days, including 6 days in the pump reservoir **PumpCart Cartridges: The maximum time at room temperature is 18 days including 4 days in the pump Storage of FIASP in Insulin Pump: • Change FIASP in the pump reservoir at least every 6 days or according to the pump user manual, whichever is shorter. • Replace the FIASP PumpCart cartridge at least every 4 days or according to the pump user manual, whichever is shorter. • Change FIASP to avoid insulin degradation or after exposure to temperatures that exceed 37°C (98.6°F). • The infusion set and infusion set insertion sites should be changed according to the manufacturers’ user manual. Storage of FIASP in Intravenous Infusion Fluids: Infusion bags prepared as indicated under Dosage and Administration ( 2.2 ) are stable at room temperature at 20°C to 25°C (68°F to 77°F) for 24 hours.