TOUJEO

1 INDICATIONS AND USAGE TOUJEO is indicated to improve glycemic control in adults and pediatric patients 6 years of age and older with diabetes mellitus. TOUJEO is a long-acting human insulin analog indicated to improve glycemic control in adults and pediatric patients 6 years and older with diabetes mellitus. ( 1 ) Limitations of Use : Not recommended for the treatment of diabetic ketoacidosis. ( 1 ) Limitations of Use: TOUJEO is not recommended for the treatment of diabetic ketoacidosis.

2 DOSAGE AND ADMINISTRATION Individualize dose based on type of diabetes, metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.1 , 2.2 , 2.3 ) Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time during the day, at the same time every day. ( 2.1 ) Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.1 ) Do not dilute or mix with any other insulin or solution. ( 2.1 ) See Full Prescribing Information for the recommended starting dosage in patients with type 2 diabetes and how to switch to TOUJEO from other insulins ( 2.3 , 2.4 ) Closely monitor glucose when changing switching to TOUJEO and during initial weeks thereafter. ( 2.4 ) 2.1 Important Administration Instructions Always check insulin labels before administration [see Warnings and Precautions (5.4) ] . Visually inspect the TOUJEO solution for particulate matter and discoloration prior to administration and only use if the solution is clear and colorless with no visible particles. Inject TOUJEO subcutaneously into the abdominal area, thigh, or deltoid. 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) , Adverse Reactions (6) ] . Use TOUJEO with caution in patients with visual impairment who may rely on audible clicks to dial their dose. Do not administer TOUJEO intravenously or in an insulin pump. Do not dilute or mix TOUJEO with any other insulin products or solutions. Never transfer TOUJEO from the cartridges of the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen into a syringe for administration [see Warnings and Precautions (5.4) ] . 2.2 General Dosing Instructions TOUJEO is available in 2 single-patient-use prefilled pens: TOUJEO SoloStar contains 450 units of TOUJEO U-300. It delivers doses in 1-unit increments and can deliver up to 80 units in a single injection. TOUJEO Max SoloStar contains 900 units of TOUJEO U-300. It delivers doses in 2-unit increments and can deliver up to 160 units in a single injection. It is recommended for patients requiring at least 20 units per day. When changing between TOUJEO SoloStar and TOUJEO Max SoloStar, if the patient's previous dose was an odd number, the dose should be increased or decreased by 1 unit to match the dose increments dialable on each prefilled pen. The dose counter of the TOUJEO SoloStar or TOUJEO Max SoloStar prefilled pen shows the number of units of TOUJEO to be injected and no conversion is required. Inject TOUJEO subcutaneously once a day at the same time of day. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2) ] . Individualize and titrate the dosage of TOUJEO based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal. Titrate the dose of TOUJEO no more frequently than every 3 to 4 days. 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 to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions (5.2) and Use in Specific Populations (8.6 , 8.7) ] . 2.3 Starting Dose in Insulin-Naive Pediatric and Adult Patients Recommended Starting Dosage in Patients with Type 1 Diabetes The recommended starting dose of TOUJEO in insulin-naive patients with type 1 diabetes is approximately one-third to one-half of the total daily insulin dose. The remainder of the total daily insulin dose should be given as a short-acting insulin and divided between each daily meal. As a general rule, 0.2 to 0.4 units of insulin per kilogram of body weight can be used to calculate the initial total daily insulin dose …

3 DOSAGE FORMS AND STRENGTHS Injection: 300 units/mL (U-300) of insulin glargine available as a clear, colorless, solution in: 1.5 mL TOUJEO SoloStar single-patient-use prefilled pen (450 units per 1.5 mL pen) 3 mL TOUJEO Max SoloStar single-patient-use prefilled pen (900 units per 3 mL pen) Injection: 300 units/mL (U-300) insulin glargine in: 1.5 mL TOUJEO SoloStar single-patient-use prefilled pen ( 3 ) 3 mL TOUJEO Max SoloStar single-patient-use prefilled pen ( 3 )

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

6 ADVERSE REACTIONS The following adverse reactions are 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 commonly associated with TOUJEO (≥5%) are: Hypoglycemia, allergic reactions, injection site reaction, lipodystrophy, pruritus, rash, edema, and weight gain. ( 6.1 , 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 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 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 304 patients with type 1 diabetes to TOUJEO with mean exposure duration of 23 weeks. The type 1 diabetes population had the following characteristics: Mean age was 46 years and mean duration of diabetes was 21 years. Fifty-five percent were male, 86% were Caucasian, 5% were Black or African American, and 5% were Hispanic. At baseline, the mean eGFR was 82 mL/min/1.73 m 2 and 35% of patients had eGFR ≥90 mL/min/1.73 m 2 . The mean BMI was 28 kg/m 2 . HbA1c at baseline was greater than or equal to 8% in 58% of patients. The data in Table 2 reflect the exposure of 1242 patients with type 2 diabetes to TOUJEO with mean exposure duration of 25 weeks. The type 2 diabetes population had the following characteristics: Mean age was 59 years and mean duration of diabetes was 13 years. Fifty-three percent were male, 88% were Caucasian, 7% were Black or African American, and 17% were Hispanic. At baseline, mean eGFR was 79 mL/min/1.73 m 2 and 27% of patients had an eGFR ≥90 mL/min/1.73 m 2 . The mean BMI was 35 kg/m 2 . HbA1c at baseline was greater than or equal to 8% in 66% of patients. TOUJEO was studied in 233 pediatric patients (6–17 years of age) with type 1 diabetes for a mean duration of 26 weeks [see Clinical Studies (14.1) ] . Common adverse reactions (occurring ≥5%) in TOUJEO-treated subjects during clinical trials in adult patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. Common adverse reactions for TOUJEO-treated pediatric subjects with type 1 diabetes mellitus were similar to the adverse reactions listed in Table 1. Hypoglycemia is discussed in a dedicated subsection below. Table 1: Adverse Reactions Occurring ≥5% in Two Pooled Clinical Trials of 26 Weeks and 16 Weeks Duration in Adults with Type 1 Diabetes TOUJEO + Mealtime Insulin "mealtime insulin" refers to insulin glulisine, insulin lispro, or insulin aspart. , % (n=304) Nasopharyngitis 12.8 Upper respiratory tract infection 9.5 Table 2: Adverse Reactions Occurring ≥5% in Three Pooled Clinical Trials of 26 Weeks Duration in Adults with Type 2 Diabetes TOUJEO one of the trials in type 2 diabetes included mealtime insulin. , % (n=1242) Nasopharyngitis 7.1 Upper respiratory tract infection 5.7 Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients treated with TOUJEO. 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 TOUJEO 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 TOUJEO adult program, severe hypoglycemia was defined as an event requiring assistance of another person to administer a resuscitative action. In the pediatric program, severe …

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with TOUJEO. Table 3: Clinically Significant Drug Interactions with TOUJEO 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, GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT-2 inhibitors. Intervention: Dosage reductions and increased frequency of glucose monitoring may be required when TOUJEO is coadministered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of TOUJEO 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 TOUJEO is coadministered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of TOUJEO 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 TOUJEO 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 TOUJEO is coadministered with these drugs. Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7 ) Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7 )

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Published studies with use of insulin glargine during pregnancy have not reported a clear association with insulin glargine and adverse developmental outcomes (see Data ) . 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 glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dose of 0.2 unit/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with 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 pregestational diabetes with a peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with a peri-conceptional HbA1c >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 increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity. Data Human Data Published data do not report a clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups. Animal Data Subcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dosage of 0.2 Units/kg/day (0.007 mg/kg/day). In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dosage of 0.2 Units/kg/day (0.007 mg/kg/day), were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal. 8.2 Lactation Risk Summary There are either no or only limited data on the presence of insulin glargine in human milk, the effects on breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TOUJEO, and any potential adverse effects on the breastfed child from TOUJEO or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of TOUJEO to improve glycemic control in pediatric patients 6 years of age and older with diabetes mellitus have been established. The use of TOUJEO for this indication is supported by evidence from an adequate and well-controlled study in 463 pediatric patients 6 to 17 years of age with type 1 diabetes mellitus [see Clinical Studies (14.2) ] and from studies in adults with diabetes mellitus [see Clinical Pharmacology (12.3) , Clinical Studies (14.3) ] . The safety and effectiveness of TOUJEO have not been establi …

12.1 Mechanism of Action The primary activity of insulin, including insulin glargine, 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 inhibits lipolysis and proteolysis and enhances protein synthesis.

11 DESCRIPTION Insulin glargine is a long-acting human insulin analog produced by recombinant DNA technology utilizing a nonpathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines remain at the C-terminus of the B-chain. Insulin glargine has a molecular weight of 6063 Da. TOUJEO (insulin glargine) injection is a sterile, clear and colorless solution for subcutaneous injection. Each mL of TOUJEO contains 300 units of insulin glargine dissolved in a clear aqueous fluid. The 1.5 mL TOUJEO SoloStar prefilled pen presentation contains the following inactive ingredients per mL: glycerin (20 mg), metacresol (2.7 mg), zinc (90 mcg), and Water for Injection, USP. The 3 mL TOUJEO Max SoloStar prefilled pen presentation contains the following inactive ingredients per mL: glycerin (20 mg), metacresol (2.7 mg), zinc (90 mcg), and Water for Injection, USP. The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. TOUJEO has a pH of approximately 4.

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3 , 5.6) ] . Mild episodes of hypoglycemia can be treated with oral glucose. Lowering the insulin dosage, and adjustments in meal patterns, or physical activity level may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon 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 Product: 50090-2193 NDC: 50090-2193-0 1.5 mL in a SYRINGE / 3 in a CARTON