Insulin glargine U-300 Max

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 described in this prescribing information, and adjust coadministered glucose-lowering therapies per standard of care [see Dosage and Administration (2.2 , 2.3) ] . 5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulin, including Insulin Glargine, U-300. Severe hypoglycemia can cause seizures, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place the patient and others at risk in situations where these abilities are important (e.g., driving, or operating other machinery). Hypoglycemia can happen suddenly, and symptoms may differ in each patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using drugs that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7) ] , or who experience recurrent hypoglycemia. The long-acting effect of an Insulin Glargine, U-300 may delay recovery from hypoglycemia compared to shorter-acting insulins. Risk Factors for Hypoglycemia The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulins, the glucose lowering effect time course of Insulin Glargine, U-300 may vary in different patients or at different times in the same patient and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2) ] . Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to concomitant drugs [see Drug Interactions (7) ] . Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6 , 8.7) ] . Risk Mitigation Strategies for Hypoglycemia Patients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended. To minimize the risk of hypoglycemia, do not administer Insulin Glargine, U-300 intravenously, intramuscularly or in an insulin pump, or dilute or mix with any other insulin products or solutions. 5.4 Hypoglycemia Due to Medication Errors Accidental mix-ups between insulin products have been reported. To avoid medication errors between Insulin Glargine, U-300 and other insulins, instruct patients to always check the insulin label before each injection. To avoid dosing errors and potential overdose, never use a syringe to remove Insulin Glargine, U-300 from the Insulin Glargine, U-300 SoloStar or Insulin Glargine, U-300 Max SoloStar prefilled pen into a syringe [see Dosage and Administration (2.4) and Warnings and Precautions (5.3) ] . 5.5 Hypersensitivity Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including Insulin Glargine, U-300. If hypersensitivity reactions occur, discontinue Insulin Glargine, U-300; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6) ] . Insulin Glargine, U-300 is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or any of the excipients in Insulin Glargine, U-300. 5.6 Hypokalemia All insulins, including Insulin Glargine, U-300, cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia, if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations). 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Insulin Glargine, U-300, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

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 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 width="75%"><caption>Table 1: Adverse Reactions Occurring &#x2265;5% in Two Pooled Clinical Trials of 26 Weeks and 16 Weeks Duration in Adults with Type 1 Diabetes</caption><col width="50%" align="left" valign="top"/><col width="50%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Insulin Glargine, U-300 + Mealtime Insulin<footnote>&quot;mealtime insulin&quot; refers to insulin glulisine, insulin lispro, or insulin aspart.</footnote>, % (n=304)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">12.8</td></tr><tr><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">9.5</td></tr></tbody></table>

<table width="75%"><caption>Table 2: Adverse Reactions Occurring &#x2265;5% in Three Pooled Clinical Trials of 26 Weeks Duration in Adults with Type 2 Diabetes</caption><col width="50%" align="left" valign="top"/><col width="50%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Insulin Glargine, U-300<footnote>one of the trials in type 2 diabetes included mealtime insulin.</footnote>, % (n=1242)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nasopharyngitis</td><td styleCode="Rrule">7.1</td></tr><tr><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">5.7</td></tr></tbody></table>