Insulin glargine U-300 Max

1 INDICATIONS AND USAGE Insulin Glargine, U-300 is indicated to improve glycemic control in adults and pediatric patients 6 years of age and older with diabetes mellitus. Insulin Glargine, U-300 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: Insulin Glargine, U-300 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. ( 2.2 ) 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 ( 2.3 ) and how to switch to Insulin Glargine, U-300 from other insulins ( 2.4 ) Closely monitor glucose when switching to Insulin Glargine, U-300 and during initial weeks thereafter. ( 2.4 ) 2.1 Important Administration Instructions Always check insulin labels before administration. This product is TOUJEO (insulin glargine). [see Warnings and Precautions (5.4) ] . Visually inspect the Insulin Glargine, U-300 solution for particulate matter and discoloration prior to administration and only use if the solution is clear and colorless with no visible particles. Inject Insulin Glargine, U-300 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 Insulin Glargine, U-300 with caution in patients with visual impairment who may rely on audible clicks to dial their dose. Do not administer Insulin Glargine, U-300 intravenously or in an insulin pump. Do not dilute or mix Insulin Glargine, U-300 with any other insulin products or solutions. Never transfer Insulin Glargine, U-300 from the cartridges of the Insulin Glargine, U-300 SoloStar or Insulin Glargine, U-300 Max SoloStar prefilled pen into a syringe for administration [see Warnings and Precautions (5.4) ] . 2.2 General Dosing Instructions Insulin Glargine, U-300 is available in 2 single-patient-use prefilled pens: The Insulin Glargine, U-300 SoloStar prefilled pen contains 450 units of insulin glargine. It delivers doses in 1-unit increments and can deliver up to 80 units in a single injection. The Insulin Glargine, U-300 Max SoloStar prefilled pen contains 900 units of insulin glargine. 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 Insulin Glargine, U-300 SoloStar and Insulin Glargine, U-300 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 Insulin Glargine, U-300 SoloStar or Insulin Glargine, U-300 Max SoloStar prefilled pen shows the number of units of Insulin Glargine, U-300 to be injected and no conversion is required. Inject Insulin Glargine, U-300 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 Insulin Glargine, U-300 based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal. Titrate the dose of Insulin Glargine, U-300 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 Dia…

5 WARNINGS AND PRECAUTIONS Never share an Insulin Glargine, U-300 SoloStar or Max SoloStar single-patient-use prefilled pen between patients, even if the needle is changed. ( 5.1 ) 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. ( 5.2 ) Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, concomitant drugs, meal pattern, physical activity, and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. ( 5.3 , 6.1 ) Hypoglycemia Due to Medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. ( 5.4 ) Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Insulin Glargine, U-300, monitor and treat if indicated. ( 5.5 , 6.1 ) Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. ( 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 Never Share an Insulin Glargine, U-300 SoloStar or Insulin Glargine, U-300 Max SoloStar Pen Between Patients Insulin Glargine, U-300 SoloStar or Insulin Glargine, U-300 Max SoloStar single-patient-use prefilled pens must never be shared between patients, even if the needle is changed. Pen sharing poses a risk for transmission of blood-borne pathogens. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen Changes in Insulin Regimen Including Changes to Administration Site 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 (5.3) ] 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 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. For patients with type 2 diabetes, dosage adjustments of concomitant oral antidiabetic products may be needed. Changing to Insulin Glargine, U-300 from other Insulin Therapies On a unit-to-unit basis, Insulin Glargine, U-300 has a lower glucose lowering effect than LANTUS [see Clinical Pharmacology (12.2) ] . In clinical trials, patients who changed to Insulin Glargine, U-300 from other basal insulins experienced higher average fasting plasma glucose levels in the first weeks of therapy compared to patients who were changed to LANTUS. Higher doses of Insulin Glargine, U-300 were required to achieve similar levels of glucose control compared to LANTUS in clinical trials [see Clinical Studies (14.1) ] . The onset of action of Insulin Glargine, U-300 develops over 6 hours following an injection. In type 1 diabetes patients treated with IV insulin, consider the longer onset of action of Insulin Glargine, U-300 before stopping IV insulin. The full glucose lowering effect may not be apparent for at least 5 days [see Dosage and Administration (2.2) and Clinical Pharmacology (12.2) ] . To minimize the risk of hyperglycemia when initiating Insulin Glargine, U-300 monitor glucose daily, titrate Insulin Glargine, U-300 as d…

4 CONTRAINDICATIONS Insulin Glargine, U-300 is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions (5.3) ] . In patients with hypersensitivity to insulin glargine or any excipients in Insulin Glargine, U-300 [see Warnings and Precautions (5.5) ] . During episodes of hypoglycemia ( 4 ) Hypersensitivity to insulin glargine or any excipients in Insulin Glargine, U-300 ( 4 )

7 DRUG INTERACTIONS Table 3 includes clinically significant drug interactions with Insulin Glargine, U-300. Table 3: Clinically Significant Drug Interactions with Insulin Glargine, U-300 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 Insulin Glargine, U-300 is coadministered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of Insulin Glargine, U-300 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 Insulin Glargine, U-300 is coadministered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Glargine, U-300 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 Insulin Glargine, U-300 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 Insulin Glargine, U-300 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 )

8.1 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.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen [see Warnings and Precautions (5.2) ] . 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 Insulin Glargine, U-300 (≥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 Insulin Glargine, U-300 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 White, 5% were Black or African American, and 5% were Hispanic or Latino. 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 body mass index (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 Insulin Glargine, U-300 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 White, 7% were Black or African American, and 17% were Hispanic or Latino. 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. Insulin Glargine, U-300 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 Insulin Glargine, U-300-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 Insulin Glargine, U-300-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 Insulin Glargine, U-300 + 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 Insulin Glargine, U-300 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 Insulin Glargine, U-300. 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 Glargine, U-300 with the incidence of hypoglycemia for other pro…