Garzulys

1 INDICATIONS AND USAGE GarzulysTM is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus. Garzulys is rapid acting human insulin analog indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus ( 1 ).

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important preparation, administration, and dosage instructions ( 2.1, 2.2, 2.3, 2.4, 2.5 ). Subcutaneous injection ( 2.2 ): Inject subcutaneously within 5-10 minutes before a meal into the abdominal area, thigh, buttocks or upper arm. Rotate injection sites within the same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis. Should generally be used in regimens with an intermediate- or long-acting insulin. Continuous Subcutaneous Infusion (Insulin Pump) ( 2.2 ): Refer to the insulin infusion pump user manual to see if Garzulys or NOVOLOG can be used with the insulin pump, in which case Garzulys can be used with the pump. Use in accordance with the insulin pump instructions for use. Administer by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. Rotate the injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not mix with other insulins or diluents in the pump. Intravenous Administration ( 2.2 ) : Dilute Garzulys to concentrations from 0.05 unit per mL to 1 unit per mL insulin aspart-fsan in infusion systems using polypropylene infusion bags. Garzulys is stable in infusion fluids such as 0.9% Sodium Chloride Injection, USP. Individualize and adjust the dosage of Garzulys based on route of administration, the individual's metabolic needs, blood glucose monitoring results and glycemic control goal ( 2.4 ). Dosage 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 ( 2.4 ). 2.1 Important Preparation and Administration Instructions Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] . Inspect Garzulys visually before use. It should appear clear and colorless. Do not use Garzulys if particulate matter or coloration is seen. Use Garzulys prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose. Do not mix Garzulys with other insulins when administering using a continuous subcutaneous infusion pump. 2.2 Preparation and Administration Instructions for the Approved Routes of Administration Subcutaneous Injection Inject Garzulys subcutaneously within 5-10 minutes before a meal into the abdominal area, thigh, buttocks or upper arm. 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 ) and Adverse Reactions ( 6.1 , 6.3 )]. Dial the Garzulys prefilled pen in 1-unit increments. Generally use Garzulys (administered by subcutaneous injection) in regimens with an intermediate- or long-acting insulin. May dilute Garzulys with Insulin Diluting Medium for Garzulys for subcutaneous injection. Diluting one part Garzulys to: Nine parts diluent will yield a concentration one-tenth that of Garzulys (equivalent to U-10). One part diluent will yield a concentration one-half that of Garzulys (equivalent to U-50). Continuous Subcutaneous Infusion (Insulin Pump) Can use this Garzulys product with the continuous subcutaneous insulin infusion pumps labeled for use with Garzulys or NOVOLOG. Refer to the insulin pump user manual to see if Garzulys or NOVOLOG can be used with the insulin pump, in which case Garzulys can be used with the pump. Use Garzulys in accordance with the insulin pump system’s instructions for use. Train patients using continuous subcutaneous insulin infusion pump therapy to administer insulin by injection and have alternate insulin therapy available in case of pump failure. Administer Garzulys by continuous sub …

3 DOSAGE FORMS AND STRENGTHS Injection: 100 units/mL (U-100) is a clear and colorless solution available as: 10 mL multiple-dose vial 3 mL single-patient-use prefilled pen Injection: 100 units/mL (U-100) of insulin aspart-fsan available as: 10 mL multiple-dose vial ( 3 ) 3 mL single-patient-use prefilled pen ( 3 )

4 CONTRAINDICATIONS Garzulys is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] In patients with hypersensitivity to insulin aspart products or any of the excipients in Garzulys [see Warnings and Precautions ( 5.5 )] During episodes of hypoglycemia ( 4 ). Hypersensitivity to insulin aspart products or any of the excipients in Garzulys.

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 observed with insulin aspart products include: hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash, and pruritus ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact Meitheal Pharmaceuticals Inc. at 1-844- 824-8426 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The safety of insulin aspart was evaluated in two treat-to-target trials of 6 months duration, conducted in patients with type 1 diabetes or type 2 diabetes [see Clinical Studies ( 14 )]. The data in Table 1 reflect the exposure of 596 patients with type 1 diabetes to insulin aspart in one clinical trial with a mean exposure duration to insulin aspart of 24 weeks. The mean age was 39 years. Fifty-one percent were male, 94% were Caucasian, 2% were Black and 4% were other races. The mean body mass index (BMI) was 25.6 kg/m 2 . The mean duration of diabetes was 15.7 years and the mean HbA 1c at baseline was 7.9%. The data in Table 2 reflect the exposure of 91 patients with type 2 diabetes to insulin aspart in one clinical trial with a mean exposure duration to insulin aspart of 24 weeks. The mean age was 57 years. Sixty-three percent were male, 76% were Caucasian, 9% were Black and 15% were other races. The mean BMI was 29.7 kg/m 2 . The mean duration of diabetes was 12.7 years and the mean HbA 1c at baseline was 8.1%. Common adverse reactions were defined as events that occurred in ≥5%, excluding hypoglycemia, of the population studied. Common adverse events that occurred at the same rate or greater for insulin aspart-treated patients than in comparator-treated patients during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are listed in Table 1 and Table 2, respectively. Table 1: Adverse reactions that occurred in ≥ 5% of Type 1 Diabetes Mellitus Adult Patients treated with insulin aspart and at the same rate or greater on insulin aspart than on comparator Insulin Aspart + NPH (%) (n= 596) Regular Human Insulin + NPH (%) (n= 286) Headache 12 10 Injury accidental 11 10 Nausea 7 5 Diarrhea 5 3 Table 2: Adverse reactions that occurred in ≥ 5% of Type 2 Diabetes Mellitus Adult Patients treated with Insulin Aspart and at the same rate or greater on Insulin Aspart than on comparator Insulin Aspart + NPH (%) (n= 91) Human Regular Insulin + NPH (%) (n= 91) Hyporeflexia 11 7 Onychomycosis 10 5 Sensory disturbance 9 7 Urinary tract infection 8 7 Chest pain 5 3 Headache 5 3 Skin disorder 5 2 Abdominal pain 5 1 Sinusitis 5 1 Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin aspart products . 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 insulin aspart 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. Severe hypoglycemia was defined as hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. The incidence of severe hypoglycemia in: Adult and pedi …

7 DRUG INTERACTIONS The table below presents clinically significant drug interactions with Garzulys. 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 analog (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when Garzulys is concomitantly administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of Garzulys 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 adjustment and increased frequency of glucose monitoring may be required when Garzulys is concomitantly administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Garzulys 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 Garzulys is concomitantly 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 Garzulys is concomitantly 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), and sulfonamide antibiotics ( 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available information from published randomized controlled trials with insulin aspart products use during the second trimester of pregnancy have not reported an association with insulin aspart products 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 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] . 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 periconceptual HbA 1c >7% and has been reported to be as high as 20 to 25% in women with a periconceptual 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 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 products during the late 2 nd trimester of pregnancy did not identify an association of insulin aspart products 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 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 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 unit/kg/day for rats and equal to the human subcutaneous dose of 1 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 insulin aspart products in human milk, the effects on the breastfed infant, or the effect on …

12.1 Mechanism of Action The primary activity of insulin, including insulin aspart products, is the 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 inhibits lipolysis and proteolysis, and enhances protein synthesis.

11 DESCRIPTION Insulin aspart-fsan is a rapid-acting human insulin analog 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 Escherichia coli . Insulin aspart-fsan has the empirical formula C 256 H 381 N 65 0 79 S 6 and a molecular weight of 5825.8 Da. Figure 1. Structural formula of insulin aspart-fsan. Garzulys (insulin aspart-fsan) injection is a sterile, clear, and colorless solution for subcutaneous or intravenous use. Each mL contains 100 units of insulin aspart-fsan and the inactive ingredients: dibasic sodium phosphate (0.997 mg), glycerin (16 mg), metacresol (1.72 mg), phenol (1.5 mg), sodium chloride (0.58 mg), zinc (19.6 mcg), and Water for Injection, USP. Garzulys has a pH of 7.2-7.6. Hydrochloric acid and/or sodium hydroxide may be added to adjust pH. Structural Formula

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.6 )] . 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 intramuscular/subcutaneous glucagon 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 Garzulys (insulin aspart-fsan) injection 100 units/mL (U-100) is available as a clear and colorless solution and is supplied as follows: Garzulys (insulin aspart-fsan) Injection 100 units/mL (U-100) Package Size NDC 10 mL Multiple-Dose Vial 1 vial per carton 71288- 904 -10 3 mL prefilled, Single-Patient-Use pen 5 pens per carton 71288- 903 -81 *Garzulys Prefilled Pen can be used with disposable needles, such as, NovoFine or NovoFine Plus. The Garzulys Prefilled Pen dials in 1-unit increments. Dispense in the original sealed carton with the enclosed Instructions for Use. Sterile, Nonpyrogenic. The container closure is not made with natural rubber latex. 16.2 Recommended Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Store unused Garzulys in a refrigerator between 2°C to 8°C (36°F to 46°F). Do not freeze Garzulys and do not use Garzulys if it has been frozen. Do not expose Garzulys to excessive heat or light. Do not withdraw Garzulys into a syringe and store for later use. Always remove and discard the needle after each injection from the Garzulys Prefilled Pen and store without a needle attached. The storage conditions are summarized in the following table: Table 9. Storage Conditions for Garzulys Vial and Prefilled Pen Garzulys presentation Not in-use (unopened) Room Temperature (up to 30°C [86°F]) Not in-use (unopened) Refrigerated (2°C to 8°C [36°F to 46°F]) In-use (opened) Room Temperature (up to 30°C [86°F]) 10 mL multiple-dose vial 28 days Until expiration date 28 days* (refrigerated/room temperature) 3 mL single-patient-use prefilled pen 28 days Until expiration date 28 days (Do not refrigerate) *For insulin pump use, the total in-use time is 19 days, including 7 days pump in-use time. Storage in External Insulin Pump: Change Garzulys in the pump reservoir at least every 7 days or according to the pump user manual instructions for Garzulys or NOVOLOG, whichever is shorter, or after exposure to temperatures that exceed 37°C (98.6°F). Storage of Diluted Garzulys Garzulys diluted with Insulin Diluting Medium for Garzulys to a concentration equivalent to U-10 or equivalent to U-50 prepared as indicated under Dosage and Administration ( 2.2 ) may remain in patient use at temperatures up to 30°C (86°F) for 28 days. Storage of Garzulys in Intravenous Infusion Fluids Infusion bags prepared as indicated under Dosage and Administration ( 2.2 ) are stable at room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the infusion.