CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 reflect the exposure of 304 patients with type diabetes to insulin glargine with mean exposure duration of 23 weeks. The type 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 m2 and 35% of patients had eGFR >=90 mL/min/1.73 m2. The mean BMI was 28 kg/m2. HbA1c at baseline was greater than or equal to 8% in 58% of patients.The data in Table reflect the exposure of 1242 patients with type diabetes to insulin glargine with mean exposure duration of 25 weeks. The type 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 m2 and 27% of patients had an eGFR >=90 mL/min/1.73 m2. The mean BMI was 35 kg/m2. HbA1c at baseline was greater than or equal to 8% in 66% of patients.Insulin glargine was studied in 233 pediatric patients (6-17 years of age) with type diabetes for mean duration of 26 weeks [see Clinical Studies (14.1)].Common adverse reactions (occurring >=5%) in insulin glargine-treated subjects during clinical trials in adult patients with type diabetes mellitus and type diabetes mellitus are listed in Table and Table 2, respectively. Common adverse reactions for insulin glargine-treated pediatric subjects with type diabetes mellitus were similar to the adverse reactions listed in Table 1. Hypoglycemia is discussed in 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 DiabetesInsulin glargine Mealtime Insulinmealtime insulin refers to insulin glulisine, insulin lispro, or insulin aspart., (n=304)Nasopharyngitis12.8Upper respiratory tract infection9.5Table 2: Adverse Reactions Occurring >=5% in Three Pooled Clinical Trials of 26 Weeks Duration in Adults with Type DiabetesInsulin glargineone of the trials in type diabetes included mealtime insulin., (n=1242)Nasopharyngitis7.1Upper respiratory tract infection5.7. HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients treated with insulin glargine. 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 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 adult program, severe hypoglycemia was defined as an event requiring assistance of another person to administer resuscitative action. In the pediatric program, severe hypoglycemia was defined as an event with semiconsciousness, unconsciousness, coma and/or convulsions in 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 diabetes receiving insulin glargine as part of multiple daily injection regimen was 6.6% at 26 weeks. The incidence of hypoglycemia with 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 diabetes receiving insulin glargine as part of multiple daily injection regimen was 6% at 26 weeks and the incidence of hypoglycemia accompanied by 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 diabetes was 5% at 26 weeks in patients receiving insulin glargine as part of multiple daily injection regimen, and 1.0% and 0.9% respectively at 26 weeks in the two studies where patients received insulin glargine as part of basal-insulin only regimen. The incidence of hypoglycemia accompanied by self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms in patients with type diabetes receiving insulin glargine ranged from 9% to 44.6% at 26 weeks and the highest risk was again seen in patients receiving insulin glargine as part of multiple daily injection regimen.. Insulin Initiation and Intensification of Glucose ControlIntensification or rapid improvement in glucose control has been associated with 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 EdemaInsulin, including insulin glargine, may cause sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy.. LipodystrophyLong-term use of insulin, including insulin glargine, 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 GainWeight gain has occurred with insulins including insulin glargine and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.. Hypersensitivity ReactionsPatients taking insulin glargine 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.

CONTRAINDICATIONS SECTION.

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 [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). During episodes of hypoglycemia (4). Hypersensitivity to insulin glargine or any excipients in INSULIN GLARGINE U-300 (4).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. INSULIN GLARGINE U-300 is indicated to improve glycemic control in adults and pediatric patients years of age and older with diabetes mellitus.. INSULIN GLARGINE U-300 is long-acting human insulin analog indicated to improve glycemic control in adults and pediatric patients 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.

ADVERSE REACTIONS SECTION.

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)] 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 (>=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.. Hypoglycemia, allergic reactions, injection site reaction, lipodystrophy, pruritus, rash, edema, and weight gain. (6.1, 6.2). 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 reflect the exposure of 304 patients with type diabetes to insulin glargine with mean exposure duration of 23 weeks. The type 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 m2 and 35% of patients had eGFR >=90 mL/min/1.73 m2. The mean BMI was 28 kg/m2. HbA1c at baseline was greater than or equal to 8% in 58% of patients.The data in Table reflect the exposure of 1242 patients with type diabetes to insulin glargine with mean exposure duration of 25 weeks. The type 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 m2 and 27% of patients had an eGFR >=90 mL/min/1.73 m2. The mean BMI was 35 kg/m2. HbA1c at baseline was greater than or equal to 8% in 66% of patients.Insulin glargine was studied in 233 pediatric patients (6-17 years of age) with type diabetes for mean duration of 26 weeks [see Clinical Studies (14.1)].Common adverse reactions (occurring >=5%) in insulin glargine-treated subjects during clinical trials in adult patients with type diabetes mellitus and type diabetes mellitus are listed in Table and Table 2, respectively. Common adverse reactions for insulin glargine-treated pediatric subjects with type diabetes mellitus were similar to the adverse reactions listed in Table 1. Hypoglycemia is discussed in 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 DiabetesInsulin glargine Mealtime Insulinmealtime insulin refers to insulin glulisine, insulin lispro, or insulin aspart., (n=304)Nasopharyngitis12.8Upper respiratory tract infection9.5Table 2: Adverse Reactions Occurring >=5% in Three Pooled Clinical Trials of 26 Weeks Duration in Adults with Type DiabetesInsulin glargineone of the trials in type diabetes included mealtime insulin., (n=1242)Nasopharyngitis7.1Upper respiratory tract infection5.7. HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients treated with insulin glargine. 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 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 adult program, severe hypoglycemia was defined as an event requiring assistance of another person to administer resuscitative action. In the pediatric program, severe hypoglycemia was defined as an event with semiconsciousness, unconsciousness, coma and/or convulsions in 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 diabetes receiving insulin glargine as part of multiple daily injection regimen was 6.6% at 26 weeks. The incidence of hypoglycemia with 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 diabetes receiving insulin glargine as part of multiple daily injection regimen was 6% at 26 weeks and the incidence of hypoglycemia accompanied by 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 diabetes was 5% at 26 weeks in patients receiving insulin glargine as part of multiple daily injection regimen, and 1.0% and 0.9% respectively at 26 weeks in the two studies where patients received insulin glargine as part of basal-insulin only regimen. The incidence of hypoglycemia accompanied by self-monitored or plasma glucose value less than 54 mg/dL regardless of symptoms in patients with type diabetes receiving insulin glargine ranged from 9% to 44.6% at 26 weeks and the highest risk was again seen in patients receiving insulin glargine as part of multiple daily injection regimen.. Insulin Initiation and Intensification of Glucose ControlIntensification or rapid improvement in glucose control has been associated with 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 EdemaInsulin, including insulin glargine, may cause sodium retention and edema, particularly if previously poor metabolic control was improved by intensified insulin therapy.. LipodystrophyLong-term use of insulin, including insulin glargine, 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 GainWeight gain has occurred with insulins including insulin glargine and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.. Hypersensitivity ReactionsPatients taking insulin glargine 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.. 6.2Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity.In 6-month study of type diabetes patients, 79% of patients who received insulin glargine 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 with antibody test at baseline remained AIA positive at month 6.In two 6-month studies in type diabetes patients, 25% of patients who received insulin glargine 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 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 with the incidence of antibodies in other studies or to other products may be misleading.. 6.3Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of insulin glargine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 sudden change to an unaffected injection site.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dosage of 0.2 Units/kg/day (0.007 mg/kg/day). The findings in female mice were not conclusive due to excessive mortality in all dose groups during the study. Histiocytomas were found at injection sites in male rats (statistically significant) and male mice (not statistically significant) in acid vehicle containing groups. These tumors were not found in female animals, in saline control, or insulin comparator groups using different vehicle. The relevance of these findings to humans is unknown.Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).In combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 Units/kg/day (0.007 mg/kg/day), maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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.. 12.2 Pharmacodynamics. Onset of ActionThe pharmacodynamic profiles for insulin glargine given subcutaneously as single dose of 0.4, 0.6, or 0.9 U/kg in euglycemic clamp study in patients with type diabetes showed that on average, the onset of action develops over hours post dose for all three single doses of insulin glargine.. Single-Dose PharmacodynamicsThe pharmacodynamics for single 0.4, 0.6, and 0.9 U/kg doses of insulin glargine in 24 patients with type diabetes mellitus was evaluated in euglycemic clamp study. On unit-to-unit basis, insulin glargine had lower maximum (GIRmax) and 24-hour glucose lowering effect (GIR-AUC0-24) compared to LANTUS. The overall glucose lowering effect of insulin glargine 0.4 U/kg was 12% of the glucose lowering effect of an equivalent dose of LANTUS. Glucose lowering at least 30% of the effect of single 0.4 U/kg dose of LANTUS was not observed until the single dose of insulin glargine exceeded 0.6 U/kg.. Multiple Once-Daily Dose PharmacodynamicsThe pharmacodynamics of insulin glargine after days of daily injection was evaluated in 30 patients with type diabetes. At steady state, the 24-hour glucose lowering effect (GIR-AUC0-24) of insulin glargine 0.4 U/kg was approximately 27% lower with different distribution profile than that of an equivalent dose of LANTUS [see Dosage and Administration (2), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)]. The glucose lowering effect of an insulin glargine dose increased with each daily administration.The pharmacodynamic profile for insulin glargine given subcutaneously as multiple once-daily subcutaneous injections of 0.4 U/kg in euglycemic clamp study in patients with type diabetes is shown in Figure 1.Figure 1: Glucose Infusion Rate in Patients with Type Diabetes in Multiple-Dose Administration of insulin glargineGlucose infusion rate: determined as amount of glucose infused to maintain constant plasma glucose levels.. Chemical Structure. 12.3 Pharmacokinetics. AbsorptionThe pharmacokinetic profiles for single 0.4, 0.6, and 0.9 U/kg doses of insulin glargine in 24 patients with type diabetes mellitus was evaluated in euglycemic clamp study. The median time to maximum serum insulin concentration was 12 (8-14), 12 (12-18), and 16 (12-20) hours, respectively. Mean serum insulin concentrations declined to the lower limit of quantitation of 5.02 uU/mL by 16, 28, and beyond 36 hours, respectively.Steady-state insulin concentrations are reached by at least days of once-daily subcutaneous administration of 0.4 U/kg to 0.6 U/kg doses of insulin glargine over days in patients with type diabetes mellitus.After subcutaneous injection of insulin glargine, the intra-subject variability, defined as the coefficient of variation for the insulin exposure during 24 hours, was 21.0% at steady state.. EliminationAfter subcutaneous injection of insulin glargine in diabetic patients, insulin glargine is metabolized at the carboxyl terminus of the B-chain with formation of two active metabolites M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). The in vitro activity of M1 and M2 were similar to that of human insulin.. Specific Populations. PediatricsPopulation pharmacokinetic analysis was conducted for insulin glargine based on concentration data of its main metabolite M1 using data from 75 pediatric patients (6 to <18 years of age) with type diabetes. The findings with regard to the effect of body weight on systemic exposure of M1 are generally consistent with findings in adults.. Elderly, Race, Sex, and ObesityEffect of age >=65, race, and sex on the pharmacokinetics of insulin glargine has not been evaluated. When weight is taken into account as covariate on clearance, BMI is not an additional covariate.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Overview of Clinical Studies. The safety and effectiveness of insulin glargine given once daily was compared to that of once-daily LANTUS in 26-week, open-label, randomized, active-control, parallel studies of 546 adult patients and 463 pediatric patients with type diabetes mellitus and 2,474 patients with type diabetes mellitus (Tables and 5). At trial end, the reduction in glycated hemoglobin (HbA1c) and fasting plasma glucose with insulin glargine titrated to goal was similar to that with LANTUS titrated to goal. At the end of the trial, depending on the patient population and concomitant therapy, patients were receiving higher dose of insulin glargine than LANTUS.. 14.2Clinical Study in Adult and Pediatric Patients with Type Diabetes. Adult Patients with Type DiabetesIn an open-label, controlled study (Study A), patients with type diabetes (n=546), were randomized to basal-bolus treatment with insulin glargine or LANTUS and treated for 26 weeks. insulin glargine and LANTUS were administered once daily in the morning (time period covering from pre-breakfast until pre-lunch) or in the evening (time period defined as prior to the evening meal until at bedtime). mealtime insulin analogue was administered before each meal. Mean age was 47 years and mean duration of diabetes was 21 years. Fifty-seven percent were male, 85% were Caucasian, 5% Black or African American, and 5% were Hispanic; 32% of patients had GFR >90 mL/min/1.73 m2. The mean BMI was approximately 27.6 kg/m2. At week 26, treatment with insulin glargine provided mean reduction in HbA1c that met the prespecified noninferiority margin of 0.4% (Table 4). Patients treated with insulin glargine used 18% more basal insulin than patients treated with LANTUS. There were no clinically important differences in glycemic control when insulin glargine was administered once daily in the morning or in the evening. There were no clinically important differences in body weight between treatment groups.Table 4: Type Diabetes Mellitus Adult Patients (insulin glargine plus mealtime insulin versus LANTUS plus mealtime insulin)Insulin glargine Mealtime Insulinmealtime insulin refers to insulin glulisine, insulin lispro or insulin aspart. LANTUS Mealtime Insulin Treatment duration26 weeksTreatment in combination withFast-acting insulin analogueNumber of subjects treated (mITTmITT: Modified intention-to-treat population.)273273HbA1c (%)Baseline mean8.138.12Adjusted mean change from baseline-0.40-0.44Adjusted mean differenceTreatment difference: insulin glargine LANTUS. [95% Confidence Interval]0.04[-0.10 to 0.18]Fasting Plasma Glucose mg/dLBaseline mean186199Adjusted mean change from baseline-17-20Adjusted mean difference [95% Confidence Interval]3[-10 to 16]. Pediatric Patients with Type DiabetesThe efficacy of insulin glargine was evaluated in 26-week, randomized, open-label, multicenter trial (Study B) in 463 pediatric patients with type diabetes mellitus. Patients were randomized to basal-bolus treatment with insulin glargine or LANTUS and treated for 26 weeks. insulin glargine and LANTUS were administered once daily in the morning or in the evening. mealtime insulin analogue was administered before each meal.The mean age of the trial population was 13 years; 31% were <12 years of age, 69% were ages >=12 years of age. The mean duration of diabetes was years. Of the 463 pediatric patients, 51% were male, 92% were White, 3% were Black or African American, and 30% were Hispanic. The mean baseline BMI percentile was 68.32.At week 26, the difference in HbA1c reduction from baseline between insulin glargine and LANTUS was 0.02% with 95% confidence interval (-0.16%; 0.20%) and met the prespecified noninferiority margin (0.3%). The results are presented in Table 5.Table 5: Type Diabetes Mellitus Pediatric Patients at 26 weeks (insulin glargine plus mealtime insulin versus LANTUS plus mealtime insulin)Insulin glargine Mealtime Insulinmealtime insulin refers to insulin glulisine, insulin lispro or insulin aspart. LANTUS Mealtime Insulin Number of subjects (ITTITT: Intention-to-treat: all randomized subjects.)233230HbA1c (%)At week 26, change in HbA1c was missing for 3.9% and 4.3% of subjects, and change in FPG was missing for 12.4% and 12.2% of subjects, in insulin glargine and LANTUS respectively. Missing values were imputed with return-to-baseline method for subjects who permanently discontinued the treatment.Baseline mean8.658.61Adjusted Mean change from baseline-0.386-0.404Adjusted Mean differenceTreatment difference: insulin glargine LANTUS. [95% Confidence Interval]0.018[-0.159, 0.195]Fasting Plasma Glucose (mg/dL)Baseline mean202.70204.51Adjusted Mean change from baseline-10.447-10.633Adjusted Mean difference [95% Confidence Interval]0.185[-18.131, 18.501]. 14.3Clinical Studies in Adult Patients with Type Diabetes. In 26-week open-label, controlled study (Study C, n=804), adults with type diabetes were randomized to once-daily treatment in the evening with either insulin glargine or LANTUS. Short-acting mealtime insulin analogues with or without metformin were also administered. The average age was 60 years. The majority of patients were White (92%) and 53% were male; 20% of patients had GFR >90 mL/min/1.73 m2. The mean BMI was approximately 36.6 kg/m2. At week 26, treatment with insulin glargine provided mean reduction in HbA1c that met the prespecified noninferiority margin of 0.4% compared to LANTUS (Table 6). Patients treated with insulin glargine used 11% more basal insulin than patients treated with LANTUS. There were no clinically important differences in body weight between treatment groups.In two open-label, controlled studies (n=1670), adults with type diabetes mellitus were randomized to either insulin glargine or LANTUS once daily for 26 weeks as part of regimen of combination therapy with noninsulin antidiabetic drugs. At the time of randomization, 808 patients were treated with basal insulin for more than months (Study D) and 862 patients were insulin-naive (Study E).In Study D, the average age was 58.2 years. The majority of patients were White (94%) and 46% were male; 33% of patients had GFR >90 mL/min/1.73 m2. The mean BMI was approximately 34.8 kg/m2. At week 26, treatment with insulin glargine provided mean reduction in HbA1c that met the prespecified noninferiority margin of 0.4% compared to LANTUS (Table 6). Patients treated with insulin glargine used 12% more basal insulin than patients treated with LANTUS. There were no clinically important differences in body weight between treatment groups.In Study E, the average age was 58 years. The majority of patients were White (78%) and 58% were male; 29% of patients had GFR >90 mL/min/1.73 m2. The mean BMI was approximately 33 kg/m2. At week 26, treatment with insulin glargine provided mean reduction in HbA1c that met the prespecified noninferiority margin compared to LANTUS (Table 6). Patients treated with insulin glargine used 15% more basal insulin than patients treated with LANTUS. There were no clinically important differences in body weight between treatment groups.Table 6: Type Diabetes Mellitus AdultStudy CStudy DStudy ETreatment duration26 weeks26 weeks26 weeksTreatment in combination withMealtime insulin analog +- metforminNoninsulin antidiabetic drugsInsulin glargineLANTUSInsulin glargineLANTUSInsulin glargineLANTUSNumber of patients treatedm-ITT population: Modified intention-to-treat population. 404400403405432430HbA1c (%)Baseline mean8.138.148.278.228.498.58Adjusted mean change from baseline-0.90-0.87-0.73-0.70-1.42-1.46Adjusted mean differenceTreatment difference: insulin glargine LANTUS. -0.03-0.030.04[95% Confidence interval][-0.14 to 0.08][-0.17 to 0.10][-0.09 to 0.17]Fasting Plasma Glucose (mg/dL)Baseline mean157160149142179184Adjusted mean change from baseline-29-30-18-22-61-68Adjusted mean difference 0.837[95% Confidence interval][-5 to 7][-3 to 9][2 to 12]. Cardiovascular SafetyNo clinical studies to establish the cardiovascular safety of insulin glargine have been conducted. cardiovascular outcomes trial, ORIGIN, has been conducted with LANTUS. It is unknown whether the results of ORIGIN can be applied to insulin glargine.The Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an open-label, randomized, 12,537 patient study that compared LANTUS to standard care on the time to first occurrence of major adverse cardiovascular event (MACE). MACE was defined as the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The incidence of MACE was similar between LANTUS and standard care in ORIGIN (Hazard Ratio [95% CI] for MACE; 1.02 [0.94, 1.11]).In the ORIGIN trial, the overall incidence of cancer (all types combined) (Hazard Ratio [95% CI]; 0.99 [0.88, 1.11]) or death from cancer (Hazard Ratio [95% CI]; 0.94 [0.77, 1.15]) was also similar between treatment groups.

DESCRIPTION SECTION.

11 DESCRIPTION. Insulin glargine is long-acting human insulin analog produced by recombinant DNA technology utilizing 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 molecular weight of 6063 Da.INSULIN GLARGINE U-300 (insulin glargine) injection is sterile, clear and colorless solution for subcutaneous injection. Each mL of INSULIN GLARGINE U-300 contains 300 units of insulin glargine dissolved in 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 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 pH of approximately 4.

DOSAGE & ADMINISTRATION SECTION.

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 diabetes and how to switch to INSULIN GLARGINE U-300 from other insulins (2.3, 2.4)Closely monitor glucose when changing switching to INSULIN GLARGINE U-300 and during initial weeks thereafter. (2.4). 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 diabetes and how to switch to INSULIN GLARGINE U-300 from other insulins (2.3, 2.4). Closely monitor glucose when changing switching to INSULIN GLARGINE U-300 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 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 syringe for administration [see Warnings and Precautions (5.4)].. Always check insulin labels before administration [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 syringe for administration [see Warnings and Precautions (5.4)].. 2.2 General Dosing Instructions. INSULIN GLARGINE U-300 is available in single-patient-use prefilled pens:INSULIN GLARGINE U-300 SoloStar contains 450 units of INSULIN GLARGINE U-300. It delivers doses in 1-unit increments and can deliver up to 80 units in single injection.INSULIN GLARGINE U-300 Max SoloStar contains 900 units of INSULIN GLARGINE U-300. It delivers doses in 2-unit increments and can deliver up to 160 units in 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 patients previous dose was an odd number, the dose should be increased or decreased by 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 day at the same time of day.During changes to patients 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 patients metabolic needs, blood glucose monitoring results, and glycemic control goal.Titrate the dose of INSULIN GLARGINE U-300 no more frequently than every to 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)].. INSULIN GLARGINE U-300 is available in single-patient-use prefilled pens:INSULIN GLARGINE U-300 SoloStar contains 450 units of INSULIN GLARGINE U-300. It delivers doses in 1-unit increments and can deliver up to 80 units in single injection.INSULIN GLARGINE U-300 Max SoloStar contains 900 units of INSULIN GLARGINE U-300. It delivers doses in 2-unit increments and can deliver up to 160 units in single injection. It is recommended for patients requiring at least 20 units per day. INSULIN GLARGINE U-300 SoloStar contains 450 units of INSULIN GLARGINE U-300. It delivers doses in 1-unit increments and can deliver up to 80 units in single injection.. INSULIN GLARGINE U-300 Max SoloStar contains 900 units of INSULIN GLARGINE U-300. It delivers doses in 2-unit increments and can deliver up to 160 units in 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 patients previous dose was an odd number, the dose should be increased or decreased by 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 day at the same time of day.. During changes to patients 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 patients metabolic needs, blood glucose monitoring results, and glycemic control goal.. Titrate the dose of INSULIN GLARGINE U-300 no more frequently than every to 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 DiabetesThe recommended starting dose of INSULIN GLARGINE U-300 in insulin-naive patients with type 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 short-acting insulin and divided between each daily meal. As 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 diabetes.The maximum glucose lowering effect of dose of INSULIN GLARGINE U-300 may take five days to fully manifest and the first INSULIN GLARGINE U-300 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.. The recommended starting dose of INSULIN GLARGINE U-300 in insulin-naive patients with type 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 short-acting insulin and divided between each daily meal. As 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 diabetes.. The maximum glucose lowering effect of dose of INSULIN GLARGINE U-300 may take five days to fully manifest and the first INSULIN GLARGINE U-300 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 DiabetesThe recommended starting dose of INSULIN GLARGINE U-300 in insulin-naive patients with type diabetes is 0.2 units per kilogram of body weight once daily.. The recommended starting dose of INSULIN GLARGINE U-300 in insulin-naive patients with type diabetes is 0.2 units per kilogram of body weight once daily.. 2.4 Starting Dose in Pediatric and Adult Patients with Either Type or Type 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 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)].. 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 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)].

DOSAGE FORMS & STRENGTHS SECTION.

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

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes clinically significant drug interactions with INSULIN GLARGINE U-300.Table 3: Clinically Significant Drug Interactions with INSULIN GLARGINE U-300Drugs That May Increase the Risk of HypoglycemiaDrugs: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-300Drugs: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-300Drugs: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 HypoglycemiaDrugs: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). 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).

GERIATRIC USE SECTION.

8.5 Geriatric Use. In controlled clinical studies, 30 of 304 (9.8%) insulin glargine-treated patients with type diabetes and 327 of 1242 (26.3%) insulin glargine-treated patients with type diabetes were >=65 years of age, among them 2.0% of the patients with type and 3.0% of the patients with type diabetes were >=75 years of age. No overall differences in safety or effectiveness of insulin glargine have been observed between patients 65 years of age and older and younger adult patients.Nevertheless, caution should be exercised when INSULIN GLARGINE U-300 is administered to geriatric patients. In geriatric patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia [see Warnings and Precautions (5.3), Adverse Reactions (6), and Clinical Studies (14)].

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of insulin glargine has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for INSULIN GLARGINE U-300 in patients with hepatic impairment [see Warnings and Precautions (5.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. INSULIN GLARGINE U-300 (insulin glargine) injection 300 units/mL is clear and colorless solution and is available as:INSULIN GLARGINE U-300Total volumeTotal units available in presentationMax dose per injectionDose incrementNDC numberPackage sizeSoloStar single-patient-use prefilled pen1.5 mL450 units80 units1 unit0955-3900-010955-3900-033 pens/packMax SoloStar single-patient-use prefilled pen3 mL900 units160 units2 units0955-2900-010955-2900-022 pens/packNeedles are not included in the packs of INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pen.BD (such as BD Ultra-Fine(R)), Ypsomed (such as Clickfine(R)) or Owen Mumford (such as Unifine(R) Pentips(R)) needlesOther brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC. can be used in conjunction with INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pen and are sold separately.A new sterile needle must be attached before each injection. 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.. 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:Not in-use (unopened)Refrigerated36F-46F (2C-8C)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 86F (30C)1.5 mL INSULIN GLARGINE U-300 SoloStar single-patient-use prefilled penUntil expiration date56 days mL INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled penUntil expiration date56 days.

IMMUNOGENICITY.

6.2Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity.In 6-month study of type diabetes patients, 79% of patients who received insulin glargine 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 with antibody test at baseline remained AIA positive at month 6.In two 6-month studies in type diabetes patients, 25% of patients who received insulin glargine 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 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 with the incidence of antibodies in other studies or to other products may be misleading.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). There are separate Instructions for Use for INSULIN GLARGINE U-300 SoloStar and INSULIN GLARGINE U-300 Max SoloStar.. Never Share an INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar Pen Between PatientsAdvise patients that they must never share INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar pen with another person even if the needle is changed. Pen sharing poses risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].. Hyperglycemia or HypoglycemiaInform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia (e.g., impaired ability to concentrate and react). This may present risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.2, 5.3)].Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].Inform patients that if they change to INSULIN GLARGINE U-300 from other basal insulins they may experience higher average fasting plasma glucose levels in the first weeks of therapy. Advise patients to monitor glucose daily when initiating INSULIN GLARGINE U-300 [see Warnings and Precautions (5.2)].. Hypoglycemia Due to Medication ErrorsInstruct patients to always check the insulin label before each injection [see Warnings and Precautions (5.4)]. The 300 units/mL (U-300) is highlighted in blue on the labels of INSULIN GLARGINE U-300 and INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pens.Inform patients that INSULIN GLARGINE U-300 (insulin glargine) 300 units/mL contains times as much insulin in mL as insulin glargine 100 units/mL. To avoid dosing errors and potential overdose, instruct patients to never use syringe to remove INSULIN GLARGINE U-300 from the INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pen [see Warnings and Precautions (5.4)].Inform patients that the dose counter of INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pen shows the number of units of INSULIN GLARGINE U-300 to be injected and no dose recalculation is required [see Dosage and Administration (2.1, 2.4)].. Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions have occurred with INSULIN GLARGINE U-300. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].

INSTRUCTIONS FOR USE SECTION.

Instructions for UseINSULIN GLARGINE U-300 SoloStar(R) (IN-su-lin-GLAR-gine)(insulin glargine)injection, for subcutaneous use1.5 mL single-patient-use prefilled penRead this firstDo not share your INSULIN GLARGINE U-300 SoloStar pen with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.INSULIN GLARGINE U-300 contains 300 units/mL of insulin glargineDo not re-use needles. If you do, you might not get your dose (underdosing) or get too much (overdosing) as the needle could block.Do not use syringe to remove insulin from your pen. If you do, you will get too much insulin. The scale on most syringes is made for U-100 (non-concentrated) insulin only.The dose selector of your INSULIN GLARGINE U-300 SoloStar pen dials by unit.People who are blind or have vision problems should not use the INSULIN GLARGINE U-300 SoloStar pen without help from person trained to use the INSULIN GLARGINE U-300 SoloStar pen.Important informationDo not use your pen if it is damaged or if you are not sure that it is working properly.Always perform safety test (see Step 3).Always carry spare pen and spare needles in case they are lost or stop working.Change (rotate) your injection sites within the area you choose for each dose (see Places to inject).Learn to injectTalk with your healthcare provider about how to inject, before using your pen.Read all of these instructions before using your pen. If you do not follow all of these instructions, you may get too much or too little insulin.Need helpIf you have any questions about your pen or about diabetes, ask your healthcare provider, go to www.winthropus.com or call sanofi-aventis at 1-800-633-1610.Extra texts you will need:a new sterile needle (not included with the pen) (see Step 2).an alcohol swab.a puncture-resistant container for used needles and pens (see Throwing your pen away).Places to injectInject your insulin exactly as your healthcare provider has shown you.Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites.Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Get to know your penStep 1: Check your penTake new pen out of the refrigerator at least hour before you inject. Cold insulin is more painful to inject.1ACheck the name and expiration date on the label of your pen.Make sure you have the correct insulin.Do not use your pen after the expiration date printed on the label. 1BPull off the pen cap.1CCheck that the insulin is clear.Do not use the pen if the insulin looks cloudy, colored or contains particles. 1DWipe the rubber seal with an alcohol swab.If you have other injector pensMaking sure you have the correct medicine is especially important if you have other injector pens.Step 2: Attach new needleDo not re-use needles. Always use new sterile needle for each injection. This helps stop blocked needles, contamination and infection.Always use needlesOther brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC. from BD (such as BD Ultra-Fine(R)), Ypsomed (such as Clickfine(R)), or Owen Mumford (such as Unifine(R) Pentips(R)).2ATake new needle and peel off the protective seal.2BKeep the needle straight and screw it onto the pen until fixed. Do not over-tighten.2CPull off the outer needle cap. Keep this for later.2DPull off the inner needle cap and throw away.Handling needlesBe careful when you are handling needles to help prevent accidental needle-stick injury. You may give other people serious infection, or get serious infection from them.Step 3: Do safety testAlways do safety test before each injection to:check your pen and the needle to make sure they are working properly.make sure that you get the correct insulin dose.If the pen is new, you must perform safety tests before you use the pen for the first time until you see insulin coming out of the needle tip. If you see insulin coming out of the needle tip, the pen is ready to use. If you do not see insulin coming out before taking your dose, you could get an underdose or no insulin at all. This could cause high blood sugar.3ASelect units by turning the dose selector until the dose pointer is at the mark between and 4.3BPress the injection button all the way in.When insulin comes out of the needle tip, your pen is working correctly.If no insulin appears:You may need to repeat this step up to times before seeing insulin.If no insulin comes out after the third time, the needle may be blocked. If this happens:- change the needle (see Step and Step 2),- then repeat the safety test (see Step 3). Do not use your pen if there is still no insulin coming out of the needle tip. Use new pen.Do not use syringe to remove insulin from your pen.If you see air bubblesYou may see air bubbles in the insulin. This is normal, they will not harm you.Step 4: Select the doseDo not select dose or press the injection button without needle attached. This may damage your pen.INSULIN GLARGINE U-300 SoloStar is made to deliver the number of insulin units that your healthcare provider prescribed. You do not need to do any dose calculations.The dose selector of your INSULIN GLARGINE U-300 SoloStar pen dials by unit.4AMake sure needle is attached and the dose is set to 0.4BTurn the dose selector until the dose pointer lines up with your dose.Set the dose by turning the dose selector to line in the dose window. Each line equals unit.The dose selector clicks as you turn it.Always check the number in the dose window to make sure you dialed the correct dose.Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin.If you turn past your dose, you can turn back down.If there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left.If you cannot select your full prescribed dose, split the dose into injections or use new pen. If you use new pen, perform safety test (see Step 3).How to read the dose windowThe dose selector dials by unit.Even numbers are shown in line with the dose pointer:30 units selectedOdd numbers are shown as line between even numbers:29 units selectedUnits of insulin in your penYour pen contains total of 450 units of insulin. You can select doses from to 80 units. Each pen contains more than dose.You can see roughly how many units of insulin are left by looking at where the plunger is on the insulin scale.Step 5: Inject your doseIf you find it hard to press the injection button in, do not force it as this may break your pen. See the section below for help.5AChoose place to inject as shown in the picture labeled Places to inject.The site you choose for the injection should be clean and dry.If your skin is dirty, clean it as instructed by your healthcare provider.5BPush the needle into your skin as shown by your healthcare provider.Do not touch the injection button yet.5CPlace your thumb on the injection button. Then press all the way in and hold.Do not press at an angle. Your thumb could block the dose selector from turning.5DKeep the injection button held in and when you see 0 in the dose window, slowly count to 5.This will make sure you get your full dose. 5EAfter holding and slowly counting to 5, release the injection button. Then remove the needle from your skin.If you find it hard to press the injection button in:Change the needle (see Step and Step 2) then do safety test (see Step 3).If you still find it hard to press in, get new pen.Do not use syringe to remove insulin from your pen.Step 6: Remove the needleTake care when handling needles to prevent needle injury and cross-infection.Do not put the inner needle cap back on.6AGrip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap.Then push firmly on.The needle can puncture the cap if it is recapped at an angle. 6BGrip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle.Try again if the needle does not come off the first time. 6CThrow away the used needle in puncture-resistant container (see Throwing your pen away at the end of this Instructions for Use). 6DPut the pen cap back on.Do not put the pen back in the refrigerator. Use byOnly use your pen for up to 56 days after its first use.How to store your penBefore first useKeep new pens in the refrigerator between 36F and 46F (2C and 8C). Do not freeze. Throw away your pen if it has been frozen (See Throwing your pen away).After first useKeep your pen at room temperature up to 86F (30C).Protect your pen from direct heat and light.Do not put your pen back in the refrigerator.Do not store your pen with the needle attached.Store your pen with the pen cap on.Keep INSULIN GLARGINE U-300 SoloStar pens and needles out of the reach of children.How to care for your penHandle your pen with careDo not drop your pen or knock it against hard surfaces.If you think that your pen may be damaged, do not try to fix it. Use new one.Protect your pen from dust and dirtYou can clean the outside of your pen by wiping it with damp cloth (water only). Do not soak, wash or lubricate your pen. This may damage it.Throwing your pen awayThe used INSULIN GLARGINE U-300 SoloStar pen may be thrown away in your household trash after you have removed the needle.Put the used needle in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) needles in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:- made of heavy-duty plastic,- can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,- upright and stable during use,- leak-resistant, and- properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.Manufactured by:sanofi-aventis U.S. LLCBridgewater, NJ 08807U.S. License No. 1752Manufactured for:Winthrop U.S.,A business of sanofi-aventis U.S. LLCBridgewater, NJ 08807A SANOFI COMPANY(C)2022 sanofi-aventis U.S. LLCThis Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: August 2022. Do not re-use needles. If you do, you might not get your dose (underdosing) or get too much (overdosing) as the needle could block.. Do not use syringe to remove insulin from your pen. If you do, you will get too much insulin. The scale on most syringes is made for U-100 (non-concentrated) insulin only.. The dose selector of your INSULIN GLARGINE U-300 SoloStar pen dials by unit.. Do not use your pen if it is damaged or if you are not sure that it is working properly.. Always perform safety test (see Step 3).. Always carry spare pen and spare needles in case they are lost or stop working.. Change (rotate) your injection sites within the area you choose for each dose (see Places to inject).. Talk with your healthcare provider about how to inject, before using your pen.. Read all of these instructions before using your pen. If you do not follow all of these instructions, you may get too much or too little insulin.. new sterile needle (not included with the pen) (see Step 2).. an alcohol swab.. puncture-resistant container for used needles and pens (see Throwing your pen away).. Inject your insulin exactly as your healthcare provider has shown you.. Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).. Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites.. Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. 1ACheck the name and expiration date on the label of your pen.Make sure you have the correct insulin.Do not use your pen after the expiration date printed on the label. Make sure you have the correct insulin.. Do not use your pen after the expiration date printed on the label. 1BPull off the pen cap.. 1CCheck that the insulin is clear.Do not use the pen if the insulin looks cloudy, colored or contains particles. Do not use the pen if the insulin looks cloudy, colored or contains particles. 1DWipe the rubber seal with an alcohol swab.. Making sure you have the correct medicine is especially important if you have other injector pens.. Do not re-use needles. Always use new sterile needle for each injection. This helps stop blocked needles, contamination and infection.. Always use needlesOther brands listed are the registered trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC. from BD (such as BD Ultra-Fine(R)), Ypsomed (such as Clickfine(R)), or Owen Mumford (such as Unifine(R) Pentips(R)).. 2ATake new needle and peel off the protective seal.. 2BKeep the needle straight and screw it onto the pen until fixed. Do not over-tighten.. 2CPull off the outer needle cap. Keep this for later.. 2DPull off the inner needle cap and throw away.. Be careful when you are handling needles to help prevent accidental needle-stick injury. You may give other people serious infection, or get serious infection from them.. check your pen and the needle to make sure they are working properly.. make sure that you get the correct insulin dose.. 3ASelect units by turning the dose selector until the dose pointer is at the mark between and 4.. 3BPress the injection button all the way in.When insulin comes out of the needle tip, your pen is working correctly.. When insulin comes out of the needle tip, your pen is working correctly.. You may need to repeat this step up to times before seeing insulin.. If no insulin comes out after the third time, the needle may be blocked. If this happens:- change the needle (see Step and Step 2),- then repeat the safety test (see Step 3). - change the needle (see Step and Step 2),. then repeat the safety test (see Step 3).. Do not use your pen if there is still no insulin coming out of the needle tip. Use new pen.. Do not use syringe to remove insulin from your pen.. You may see air bubbles in the insulin. This is normal, they will not harm you.. Do not select dose or press the injection button without needle attached. This may damage your pen.. INSULIN GLARGINE U-300 SoloStar is made to deliver the number of insulin units that your healthcare provider prescribed. You do not need to do any dose calculations.. The dose selector of your INSULIN GLARGINE U-300 SoloStar pen dials by unit.. 4AMake sure needle is attached and the dose is set to 0.. 4BTurn the dose selector until the dose pointer lines up with your dose.Set the dose by turning the dose selector to line in the dose window. Each line equals unit.The dose selector clicks as you turn it.Always check the number in the dose window to make sure you dialed the correct dose.Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin.If you turn past your dose, you can turn back down.If there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left.If you cannot select your full prescribed dose, split the dose into injections or use new pen. If you use new pen, perform safety test (see Step 3).. Set the dose by turning the dose selector to line in the dose window. Each line equals unit.. The dose selector clicks as you turn it.. Always check the number in the dose window to make sure you dialed the correct dose.. Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin.. If you turn past your dose, you can turn back down.. If there are not enough units left in your pen for your dose, the dose selector will stop at the number of units left.. If you cannot select your full prescribed dose, split the dose into injections or use new pen. If you use new pen, perform safety test (see Step 3).. Your pen contains total of 450 units of insulin. You can select doses from to 80 units. Each pen contains more than dose.. You can see roughly how many units of insulin are left by looking at where the plunger is on the insulin scale.. 5AChoose place to inject as shown in the picture labeled Places to inject.The site you choose for the injection should be clean and dry.If your skin is dirty, clean it as instructed by your healthcare provider.. The site you choose for the injection should be clean and dry.. If your skin is dirty, clean it as instructed by your healthcare provider.. 5BPush the needle into your skin as shown by your healthcare provider.Do not touch the injection button yet.. Do not touch the injection button yet.. 5CPlace your thumb on the injection button. Then press all the way in and hold.Do not press at an angle. Your thumb could block the dose selector from turning.. Do not press at an angle. Your thumb could block the dose selector from turning.. 5DKeep the injection button held in and when you see 0 in the dose window, slowly count to 5.This will make sure you get your full dose. This will make sure you get your full dose. 5EAfter holding and slowly counting to 5, release the injection button. Then remove the needle from your skin.. Change the needle (see Step and Step 2) then do safety test (see Step 3).. If you still find it hard to press in, get new pen.. Do not use syringe to remove insulin from your pen.. Take care when handling needles to prevent needle injury and cross-infection.. Do not put the inner needle cap back on.. 6AGrip the widest part of the outer needle cap. Keep the needle straight and guide it into the outer needle cap.Then push firmly on.The needle can puncture the cap if it is recapped at an angle. The needle can puncture the cap if it is recapped at an angle. 6BGrip and squeeze the widest part of the outer needle cap. Turn your pen several times with your other hand to remove the needle.Try again if the needle does not come off the first time. Try again if the needle does not come off the first time. 6CThrow away the used needle in puncture-resistant container (see Throwing your pen away at the end of this Instructions for Use). 6DPut the pen cap back on.Do not put the pen back in the refrigerator. Do not put the pen back in the refrigerator. Only use your pen for up to 56 days after its first use.. Keep new pens in the refrigerator between 36F and 46F (2C and 8C). Do not freeze. Throw away your pen if it has been frozen (See Throwing your pen away).. Keep your pen at room temperature up to 86F (30C).. Protect your pen from direct heat and light.. Do not put your pen back in the refrigerator.. Do not store your pen with the needle attached.. Store your pen with the pen cap on.. Keep INSULIN GLARGINE U-300 SoloStar pens and needles out of the reach of children.. Do not drop your pen or knock it against hard surfaces.. If you think that your pen may be damaged, do not try to fix it. Use new one.. You can clean the outside of your pen by wiping it with damp cloth (water only). Do not soak, wash or lubricate your pen. This may damage it.. The used INSULIN GLARGINE U-300 SoloStar pen may be thrown away in your household trash after you have removed the needle.. Put the used needle in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) needles in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:- made of heavy-duty plastic,- can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,- upright and stable during use,- leak-resistant, and- properly labeled to warn of hazardous waste inside the container. - made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. upright and stable during use,. leak-resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image. Image.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for INSULIN GLARGINE U-300, and any potential adverse effects on the breastfed child from INSULIN GLARGINE U-300 or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dosage of 0.2 Units/kg/day (0.007 mg/kg/day). The findings in female mice were not conclusive due to excessive mortality in all dose groups during the study. Histiocytomas were found at injection sites in male rats (statistically significant) and male mice (not statistically significant) in acid vehicle containing groups. These tumors were not found in female animals, in saline control, or insulin comparator groups using different vehicle. The relevance of these findings to humans is unknown.Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).In combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 Units/kg/day (0.007 mg/kg/day), maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

OVERDOSAGE SECTION.

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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 1.5 mL Pen Carton. Winthrop SANOFI COMPANYNDC 0955-3900-03Rx onlyInsulin glargine U-300 SoloStar(R) injectionFor Single Patient Use Only300 units/mL (U-300)For subcutaneous use onlySolution for injection in disposable insulin delivery deviceDo not remove insulin with syringeAlways use new needle Do not mix with other insulinsUse only if solution is clear and colorless with no particles visibleUse within 56 days after openingNeedles not included (see back panel)Three 1.5 mL prefilled pens Dispense in this sealed cartonsanofi. PRINCIPAL DISPLAY PANEL 1.5 mL Pen Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of INSULIN GLARGINE U-300 to improve glycemic control in pediatric patients years of age and older with diabetes mellitus have been established.The use of INSULIN GLARGINE U-300 for this indication is supported by evidence from an adequate and well-controlled study in 463 pediatric patients to 17 years of age with type 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 INSULIN GLARGINE U-300 have not been established in pediatric patients less than years of age.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Onset of ActionThe pharmacodynamic profiles for insulin glargine given subcutaneously as single dose of 0.4, 0.6, or 0.9 U/kg in euglycemic clamp study in patients with type diabetes showed that on average, the onset of action develops over hours post dose for all three single doses of insulin glargine.. Single-Dose PharmacodynamicsThe pharmacodynamics for single 0.4, 0.6, and 0.9 U/kg doses of insulin glargine in 24 patients with type diabetes mellitus was evaluated in euglycemic clamp study. On unit-to-unit basis, insulin glargine had lower maximum (GIRmax) and 24-hour glucose lowering effect (GIR-AUC0-24) compared to LANTUS. The overall glucose lowering effect of insulin glargine 0.4 U/kg was 12% of the glucose lowering effect of an equivalent dose of LANTUS. Glucose lowering at least 30% of the effect of single 0.4 U/kg dose of LANTUS was not observed until the single dose of insulin glargine exceeded 0.6 U/kg.. Multiple Once-Daily Dose PharmacodynamicsThe pharmacodynamics of insulin glargine after days of daily injection was evaluated in 30 patients with type diabetes. At steady state, the 24-hour glucose lowering effect (GIR-AUC0-24) of insulin glargine 0.4 U/kg was approximately 27% lower with different distribution profile than that of an equivalent dose of LANTUS [see Dosage and Administration (2), Warnings and Precautions (5.2), and Clinical Pharmacology (12.3)]. The glucose lowering effect of an insulin glargine dose increased with each daily administration.The pharmacodynamic profile for insulin glargine given subcutaneously as multiple once-daily subcutaneous injections of 0.4 U/kg in euglycemic clamp study in patients with type diabetes is shown in Figure 1.Figure 1: Glucose Infusion Rate in Patients with Type Diabetes in Multiple-Dose Administration of insulin glargineGlucose infusion rate: determined as amount of glucose infused to maintain constant plasma glucose levels.. Chemical Structure.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionThe pharmacokinetic profiles for single 0.4, 0.6, and 0.9 U/kg doses of insulin glargine in 24 patients with type diabetes mellitus was evaluated in euglycemic clamp study. The median time to maximum serum insulin concentration was 12 (8-14), 12 (12-18), and 16 (12-20) hours, respectively. Mean serum insulin concentrations declined to the lower limit of quantitation of 5.02 uU/mL by 16, 28, and beyond 36 hours, respectively.Steady-state insulin concentrations are reached by at least days of once-daily subcutaneous administration of 0.4 U/kg to 0.6 U/kg doses of insulin glargine over days in patients with type diabetes mellitus.After subcutaneous injection of insulin glargine, the intra-subject variability, defined as the coefficient of variation for the insulin exposure during 24 hours, was 21.0% at steady state.. EliminationAfter subcutaneous injection of insulin glargine in diabetic patients, insulin glargine is metabolized at the carboxyl terminus of the B-chain with formation of two active metabolites M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). The in vitro activity of M1 and M2 were similar to that of human insulin.. Specific Populations. PediatricsPopulation pharmacokinetic analysis was conducted for insulin glargine based on concentration data of its main metabolite M1 using data from 75 pediatric patients (6 to <18 years of age) with type diabetes. The findings with regard to the effect of body weight on systemic exposure of M1 are generally consistent with findings in adults.. Elderly, Race, Sex, and ObesityEffect of age >=65, race, and sex on the pharmacokinetics of insulin glargine has not been evaluated. When weight is taken into account as covariate on clearance, BMI is not an additional covariate.

POSTMARKETING EXPERIENCE SECTION.

6.3Postmarketing Experience The following additional adverse reactions have been identified during postapproval use of insulin glargine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 sudden change to an unaffected injection site.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPublished studies with use of insulin glargine during pregnancy have not reported 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 peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with 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 RiskHypoglycemia 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 DataPublished data do not report 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 DataSubcutaneous 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.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. The effect of kidney impairment on the pharmacokinetics of insulin glargine has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with kidney failure. Frequent glucose monitoring and dose adjustment may be necessary for insulin glargine in patients with kidney impairment [see Warnings and Precautions (5.3)].

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: August 2022Patient InformationINSULIN GLARGINE U-300 (IN-su-lin-GLAR-gine)(insulin glargine)injection, for subcutaneous use300 units/mL (U-300)Do not share your INSULIN GLARGINE U-300 SoloStar(R) or INSULIN GLARGINE U-300 Max SoloStar(R) pen with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.What is INSULIN GLARGINE U-300INSULIN GLARGINE U-300 is long-acting man-made insulin used to control high blood sugar in adults and children who are years of age and older with diabetes mellitus.INSULIN GLARGINE U-300 is not for the treatment of diabetic ketoacidosis.It is not known if INSULIN GLARGINE U-300 is safe and effective in children under years of age.Who should not use INSULIN GLARGINE U-300Do not use INSULIN GLARGINE U-300 if you:are having an episode of low blood sugar (hypoglycemia).have an allergy to insulin glargine or any of the ingredients in INSULIN GLARGINE U-300. See the end of this Patient Information leaflet for complete list of ingredients in INSULIN GLARGINE U-300.What should tell my healthcare provider before using INSULIN GLARGINE U-300Before using INSULIN GLARGINE U-300, tell your healthcare provider about all your medical conditions, including if you:have liver or kidney problems.take other medicines, especially ones called TZDs (thiazolidinediones).have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with INSULIN GLARGINE U-300.are pregnant, planning to become pregnant, or are breastfeeding. It is not known if INSULIN GLARGINE U-300 may harm your unborn or breastfeeding baby.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Before you start using INSULIN GLARGINE U-300, talk to your healthcare provider about low blood sugar and how to manage it.How should use INSULIN GLARGINE U-300INSULIN GLARGINE U-300 is available in single-patient-use prefilled pens: INSULIN GLARGINE U-300 SoloStar and INSULIN GLARGINE U-300 Max SoloStar. Your healthcare provider will tell you which INSULIN GLARGINE U-300 Pen is right for you.Read the detailed Instructions for Use that come with your INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pen.Use INSULIN GLARGINE U-300 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much INSULIN GLARGINE U-300 to use and when to use it.Know the amount of INSULIN GLARGINE U-300 you use. Do not change the amount of INSULIN GLARGINE U-300 you use unless your healthcare provider tells you to.Check your insulin label each time you give your injection to make sure you are using the correct insulin.Do not use syringe to remove INSULIN GLARGINE U-300 from your INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pen. This can cause you to give yourself too much insulin. INSULIN GLARGINE U-300 has times as much insulin (300 units/mL) in mL as compared to insulin glargine (U-100 units/mL) pens.Do not re-use needles. Always use new needle for each injection. Reusing needles increases your chance of having blocked needles, which can cause you to get the wrong dose of INSULIN GLARGINE U-300. Using new needle for each injection also lowers your risk of getting an infection. If your needle is blocked, follow the instructions in Step of the Instructions for Use.INSULIN GLARGINE U-300 should be used time each day and at the same time each day.INSULIN GLARGINE U-300 is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).Do not use INSULIN GLARGINE U-300 in an insulin pump or inject INSULIN GLARGINE U-300 into your vein (intravenously).Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites.Do not use the exact same spot for each injection.Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Do not mix INSULIN GLARGINE U-300 with any other type of insulin or liquid medicine.Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.Keep INSULIN GLARGINE U-300 and all medicines out of the reach of children.Your dose of INSULIN GLARGINE U-300 may need to change because of:a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.What should avoid while using INSULIN GLARGINE U-300While using INSULIN GLARGINE U-300 do not:drive or operate heavy machinery, until you know how INSULIN GLARGINE U-300 affects you.drink alcohol or use over-the-counter medicines that contain alcohol.What are the possible side effects of INSULIN GLARGINE U-300INSULIN GLARGINE U-300 may cause serious side effects that can lead to death, including:low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, and hunger. severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of severe allergic reaction:a rash over your whole body, trouble breathing, fast heartbeat, or sweating.low potassium in your blood (hypokalemia).heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with INSULIN GLARGINE U-300 may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with INSULIN GLARGINE U-300. Your healthcare provider should monitor you closely while you are taking TZDs with INSULIN GLARGINE U-300. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:shortness of breath, swelling of your ankles or feet, sudden weight gain.Treatment with TZDs and INSULIN GLARGINE U-300 may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.Get emergency medical help if you have:trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.The most common side effects of INSULIN GLARGINE U-300 include:low blood sugar (hypoglycemia), weight gain, itching, rash, swelling, allergic reactions, including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy).These are not all the possible side effects of INSULIN GLARGINE U-300. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of INSULIN GLARGINE U-300.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use INSULIN GLARGINE U-300 for condition for which it was not prescribed. Do not give INSULIN GLARGINE U-300 to other people, even if they have the same symptoms that you have. It may harm them.This Patient Information leaflet summarizes the most important information about INSULIN GLARGINE U-300. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about INSULIN GLARGINE U-300 that is written for health professionals.What are the ingredients in INSULIN GLARGINE U-300Active ingredient: insulin glargineInactive ingredients: glycerin, metacresol, zinc and Water for Injection, USP. Hydrochloric acid and sodium hydroxide may be added to adjust the pH.Manufactured by: sanofi-aventis U.S. LLC, Bridgewater, NJ 08807,U.S. License No. 1752Manufactured for: Winthrop U.S., business of sanofi-aventis U.S., LLC, Bridgewater, NJ 08807, SANOFI COMPANYFor more information about Insulin glargine call 1-800-633-1610 or go to www.winthropus.com.. INSULIN GLARGINE U-300 is long-acting man-made insulin used to control high blood sugar in adults and children who are years of age and older with diabetes mellitus.. INSULIN GLARGINE U-300 is not for the treatment of diabetic ketoacidosis.. It is not known if INSULIN GLARGINE U-300 is safe and effective in children under years of age.. are having an episode of low blood sugar (hypoglycemia).. have an allergy to insulin glargine or any of the ingredients in INSULIN GLARGINE U-300. See the end of this Patient Information leaflet for complete list of ingredients in INSULIN GLARGINE U-300.. have liver or kidney problems.. take other medicines, especially ones called TZDs (thiazolidinediones).. have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with INSULIN GLARGINE U-300.. are pregnant, planning to become pregnant, or are breastfeeding. It is not known if INSULIN GLARGINE U-300 may harm your unborn or breastfeeding baby.. INSULIN GLARGINE U-300 is available in single-patient-use prefilled pens: INSULIN GLARGINE U-300 SoloStar and INSULIN GLARGINE U-300 Max SoloStar. Your healthcare provider will tell you which INSULIN GLARGINE U-300 Pen is right for you.. Read the detailed Instructions for Use that come with your INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pen.. Use INSULIN GLARGINE U-300 exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much INSULIN GLARGINE U-300 to use and when to use it.. Know the amount of INSULIN GLARGINE U-300 you use. Do not change the amount of INSULIN GLARGINE U-300 you use unless your healthcare provider tells you to.. Check your insulin label each time you give your injection to make sure you are using the correct insulin.. Do not use syringe to remove INSULIN GLARGINE U-300 from your INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled pen. This can cause you to give yourself too much insulin. INSULIN GLARGINE U-300 has times as much insulin (300 units/mL) in mL as compared to insulin glargine (U-100 units/mL) pens.. Do not re-use needles. Always use new needle for each injection. Reusing needles increases your chance of having blocked needles, which can cause you to get the wrong dose of INSULIN GLARGINE U-300. Using new needle for each injection also lowers your risk of getting an infection. If your needle is blocked, follow the instructions in Step of the Instructions for Use.. INSULIN GLARGINE U-300 should be used time each day and at the same time each day.. INSULIN GLARGINE U-300 is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).. Do not use INSULIN GLARGINE U-300 in an insulin pump or inject INSULIN GLARGINE U-300 into your vein (intravenously).. Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting pits or thickening of the skin (lipodystrophy) and lumps in the skin (localized cutaneous amyloidosis) at the injection sites.Do not use the exact same spot for each injection.Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Do not use the exact same spot for each injection.. Do not inject where the skin has pits, is thickened, or has lumps.. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. Do not mix INSULIN GLARGINE U-300 with any other type of insulin or liquid medicine.. Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.. change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.. drive or operate heavy machinery, until you know how INSULIN GLARGINE U-300 affects you.. drink alcohol or use over-the-counter medicines that contain alcohol.. low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, and hunger. dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, and hunger.. severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of severe allergic reaction:a rash over your whole body, trouble breathing, fast heartbeat, or sweating.. rash over your whole body, trouble breathing, fast heartbeat, or sweating.. low potassium in your blood (hypokalemia).. heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with INSULIN GLARGINE U-300 may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with INSULIN GLARGINE U-300. Your healthcare provider should monitor you closely while you are taking TZDs with INSULIN GLARGINE U-300. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:shortness of breath, swelling of your ankles or feet, sudden weight gain.Treatment with TZDs and INSULIN GLARGINE U-300 may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.. shortness of breath, swelling of your ankles or feet, sudden weight gain.. trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.. low blood sugar (hypoglycemia), weight gain, itching, rash, swelling, allergic reactions, including reactions at your injection site, skin thickening or pits at the injection site (lipodystrophy).. Active ingredient: insulin glargine. Inactive ingredients: glycerin, metacresol, zinc and Water for Injection, USP. Hydrochloric acid and sodium hydroxide may be added to adjust the pH.

SPL UNCLASSIFIED SECTION.

Limitations of Use:INSULIN GLARGINE U-300 is not recommended for the treatment of diabetic ketoacidosis.

STORAGE AND HANDLING SECTION.

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:Not in-use (unopened)Refrigerated36F-46F (2C-8C)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 86F (30C)1.5 mL INSULIN GLARGINE U-300 SoloStar single-patient-use prefilled penUntil expiration date56 days mL INSULIN GLARGINE U-300 Max SoloStar single-patient-use prefilled penUntil expiration date56 days.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryPublished studies with use of insulin glargine during pregnancy have not reported 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 peri-conceptional HbA1c >7 and has been reported to be as high as 20% to 25% in women with 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 RiskHypoglycemia 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 DataPublished data do not report 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 DataSubcutaneous 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 SummaryThere 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 mothers clinical need for INSULIN GLARGINE U-300, and any potential adverse effects on the breastfed child from INSULIN GLARGINE U-300 or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of INSULIN GLARGINE U-300 to improve glycemic control in pediatric patients years of age and older with diabetes mellitus have been established.The use of INSULIN GLARGINE U-300 for this indication is supported by evidence from an adequate and well-controlled study in 463 pediatric patients to 17 years of age with type 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 INSULIN GLARGINE U-300 have not been established in pediatric patients less than years of age.. 8.5 Geriatric Use. In controlled clinical studies, 30 of 304 (9.8%) insulin glargine-treated patients with type diabetes and 327 of 1242 (26.3%) insulin glargine-treated patients with type diabetes were >=65 years of age, among them 2.0% of the patients with type and 3.0% of the patients with type diabetes were >=75 years of age. No overall differences in safety or effectiveness of insulin glargine have been observed between patients 65 years of age and older and younger adult patients.Nevertheless, caution should be exercised when INSULIN GLARGINE U-300 is administered to geriatric patients. In geriatric patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia [see Warnings and Precautions (5.3), Adverse Reactions (6), and Clinical Studies (14)].. 8.6 Renal Impairment. The effect of kidney impairment on the pharmacokinetics of insulin glargine has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with kidney failure. Frequent glucose monitoring and dose adjustment may be necessary for insulin glargine in patients with kidney impairment [see Warnings and Precautions (5.3)].. 8.7 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of insulin glargine has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for INSULIN GLARGINE U-300 in patients with hepatic impairment [see Warnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Never share an INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 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 patients 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, 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). Never share an INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 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 patients 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, 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 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 SiteChanges 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 sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)].Make any changes to patients 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 diabetes, dosage adjustments of concomitant oral antidiabetic products may be needed.. Changing to INSULIN GLARGINE U-300 from other Insulin TherapiesOn unit-to-unit basis, insulin glargine has lower glucose lowering effect than LANTUS [see Clinical Pharmacology (12.2)]. In clinical trials, patients who changed to insulin glargine 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 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 develops over hours following an injection. In type diabetes patients treated with IV insulin, consider the longer onset of action of insulin glargine before stopping IV insulin. The full glucose lowering effect may not be apparent for at least 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 INSULIN GLARGINE U-300 may delay recovery from hypoglycemia compared to shorter-acting insulins.. Risk Factors for HypoglycemiaThe 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 HypoglycemiaPatients 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 INSULIN GLARGINE U-300 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 syringe to remove INSULIN GLARGINE U-300 from the INSULIN GLARGINE U-300 SoloStar or INSULIN GLARGINE U-300 Max SoloStar prefilled pen into 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 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 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.