INSULIN GLARGINE U-300 MAX

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. Insulin Glargine, U-300 injection is a sterile, clear and colorless solution for subcutaneous injection. Each mL of Insulin Glargine, U-300 contains 300 units of insulin glargine dissolved in a clear aqueous fluid. The 1.5 mL Insulin Glargine, U-300 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 Insulin Glargine, U-300 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. Insulin Glargine, U-300 has a pH of approximately 4.

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.

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 Diabetes The recommended starting dose of Insulin Glargine, U-300 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 in insulin-naive patients with type 1 diabetes. The maximum glucose lowering effect of a dose of Insulin Glargine, U-300 may take five days to fully manifest and the first dose may be insufficient to cover metabolic needs in the first 24 hours of use [see Clinical Pharmacology (12.2) ] . When initiating Insulin Glargine, U-300, monitor glucose daily. Recommended Starting Dosage in Patients with Type 2 Diabetes The recommended starting dose of Insulin Glargine, U-300 in insulin-naive patients with type 2 diabetes is 0.2 units per kilogram of body weight once daily. 2.4 Starting Dose in Pediatric and Adult Patients with Either Type 1 or Type 2 Diabetes Already on Insulin Therapy Dosage adjustments are recommended to lower the risk of hypoglycemia when switching patients to Insulin Glargine, U-300 from another insulin therapy [see Warnings and Precautions (5.3) ]. For patients currently on once-daily long or intermediate-acting insulin, start Insulin Glargine, U-300 at the same unit dose as the once-daily long-acting insulin dose. For patients controlled on LANTUS (insulin glargine, 100 units/mL), expect that a higher daily dose of Insulin Glargine, U-300 will be needed to maintain the same level of glycemic control [see Clinical Pharmacology (12.2) and Clinical Studies (14.1) ] . For patients currently on twice-daily long or intermediate-acting insulin, start Insulin Glargine, U-300 at 80% of the total daily NPH or insulin detemir twice-daily dosage. When switching patients to Insulin Glargine, U-300, monitor glucose frequently in the first weeks of therapy [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2) ] .

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 )

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 products may be misleading and also may not be representative of hypoglycemia rates that will occur in clinical practice. In the Insulin Glargine, U-300 adult program, severe hypoglycemia was defined as an event requiring assistance of another person to administer a resuscitative action. In the pediatric program, severe hypoglycemia was defined as an event with semiconsciousness, unconsciousness, coma and/or convulsions in a patient who had altered mental status and could not assist in his own care, and who may have required glucagon or intravenous glucose. The incidence of severe hypoglycemia in adult patients with type 1 diabetes receiving Insulin Glargine, U-300 as part of a multiple daily injection regimen was 6.6% at 26 weeks. The incidence of hypoglycemia with a glucose level less than 54 mg/dL with or without symptoms was 77.7% at 26 weeks. The incidence of severe hypoglycemia in pediatric patients with type 1 diabetes receiving Insulin Glargine, U-300 as part of a multiple daily injection regimen was 6% at 26 weeks and the incidence of hypoglycemia accompanied by a self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms was 80.3%. The incidence of severe hypoglycemia in adult patients with type 2 diabetes was 5% at 26 weeks in patients receiving Insulin Glargine, U-300 as part of a multiple daily injection regimen, and 1.0% and 0.9% respectively at 26 weeks in the two studies where patients received Insulin Glargine, U-300 as part of a basal-insulin only regimen. The incidence of hypoglycemia accompanied by a self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms in patients with type 2 diabetes receiving Insulin Glargine, U-300 ranged from 9% to 44.6% at 26 weeks and the highest risk was again seen in patients receiving Insulin Glargine, U-300 as part of a multiple daily injection regimen. 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. Peripheral Edema Insulin, including Insulin Glargine, U-300, may cause sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy. Lipodystrophy Long-term use of insulin, including Insulin Glargine, U-300, can cause lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients and may affect insulin absorption [see Dosage and Administration (2.1) ] . Weight Gain Weight gain has occurred with insulins including Insulin Glargine, U-300 and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Hypersensitivity Reactions Patients taking Insulin Glargine, U-300 experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. In a 6-month study of type 1 diabetes patients, 79% of patients who received Insulin Glargine, U-300 once daily were positive for anti-insulin antibodies (AIA) at least once during the study, including 62% that were positive at baseline and 44% of patients who developed antidrug antibody (i.e., anti-insulin glargine antibody [ADA]) during the study. Eighty percent of the AIA-positive patients on Insulin Glargine, U-300 with antibody test at baseline remained AIA positive at month 6. In two 6-month studies in type 2 diabetes patients, 25% of patients who received Insulin Glargine, U-300 once daily were positive for AIA at least once during the study, including 42% who were positive at baseline and 20% of patients who developed ADA during the study. Ninety percent of the AIA-positive patients on Insulin Glargine, U-300 with antibody test at baseline, remained AIA positive at month 6. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to Insulin Glargine, U-300 with the incidence of antibodies in other studies or to other products may be misleading. 6.3 Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of Insulin Glargine, U-300. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

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 )

16.2 Storage Dispense in the original sealed carton with the enclosed Instructions for Use. Insulin Glargine, U-300 SoloStar or Insulin Glargine, U-300 Max SoloStar prefilled pen should not be stored in the freezer and should not be allowed to freeze. Discard Insulin Glargine, U-300 prefilled pen if it has been frozen. Protect Insulin Glargine, U-300 SoloStar/ Insulin Glargine, U-300 Max SoloStar from direct heat and light. Storage conditions are summarized in the following table: Insulin Glargine, U-300 Not in-use (unopened) Refrigerated 36°F–46°F (2°C–8°C) In-use (opened) To prevent degradation, always store the prefilled pens with the cap on during in-use period. Room temperature only (Do not refrigerate) up to 86°F (30°C) 1.5 mL SoloStar single-patient-use prefilled pen Until expiration date 56 days 3 mL Max SoloStar single-patient-use prefilled pen Until expiration date 56 days