6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions (5.3)] Medication Errors [see Warnings and Precautions (5.4)] Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)] Hypokalemia [see Warnings and Precautions (5.6)] Adverse reactions commonly associated with TOUJEO (≥5%) are: Hypoglycemia, allergic reactions, injection site reaction, lipodystrophy, pruritus, rash, edema and weight gain. (6.1, 6.2) To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates actually observed in clinical practice. The data in Table 1 reflect the exposure of 304 patients with type 1 diabetes to TOUJEO with mean exposure duration of 23 weeks. The type 1 diabetes population had the following characteristics: Mean age was 46 years and mean duration of diabetes was 21 years. Fifty-five percent were male, 86% were Caucasian, 5% were Black or African American, and 5% were Hispanic. At baseline, the mean eGFR was 82 mL/min/1.73 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 or equal to 8% in 58% of patients. The data in Table 2 reflect the exposure of 1242 patients with type 2 diabetes to TOUJEO with mean exposure duration of 25 weeks. The type 2 diabetes population had the following characteristics: Mean age was 59 years and mean duration of diabetes was 13 years. Fifty-three percent were male, 88% were Caucasian, 7% were Black or African American, and 17% were Hispanic. At baseline, mean eGFR was 79 mL/min/1.73 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 or equal to 8% in 66% of patients. Common adverse reactions were defined as reactions occurring in ≥5% of the population studied. Common adverse reactions occurring for TOUJEO-treated subjects during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in Table 1 and Table 2, respectively. Hypoglycemia is discussed in a dedicated subsection below. Table 1: Adverse Reactions in Two Pooled Clinical Trials of 26 Weeks and 16 Weeks Duration in Adults with Type 1 Diabetes (with incidence ≥5%) TOUJEO + Mealtime Insulin"mealtime insulin" refers to insulin glulisine, insulin lispro, or insulin aspart., % (n=304) Nasopharyngitis 12.8 Upper respiratory tract infection 9.5 Table 2: Adverse Reactions in Three Pooled Clinical Trials of 26 Weeks Duration in Adults with Type 2 Diabetes (with incidence ≥5%) TOUJEOone of the trials in type 2 diabetes included mealtime insulin., % (n=1242) Nasopharyngitis 7.1 Upper respiratory tract infection 5.7 Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including TOUJEO [see Warnings and Precautions (5.3)]. In the TOUJEO program, severe hypoglycemia was defined as an event requiring assistance of another person to administer a resuscitative action and documented symptomatic hypoglycemia was defined as an event with typical symptoms of hypoglycemia accompanied by a self-monitored or plasma glucose value equal to or less than 54 mg/dL. The incidence of severe hypoglycemia in patients with type 1 diabetes receiving TOUJEO as part of a multiple daily injection regimen was 6.6% at 26 weeks. The incidence of documented symptomatic hypoglycemia was 69% at 26 weeks. There were no clinically important differences in hypoglycemia between TOUJEO and LANTUS among type 1 diabetes patients. The incidence of severe hypoglycemia in patients with type 2 diabetes was 5% at 26 weeks in patients receiving TOUJEO as part of a multiple daily injection regimen, and 1.0% and 0.9% respectively at 26 weeks in the two studies where patients received TOUJEO as part of a basal-insulin only regimen. The incidence of documented symptomatic hypoglycemia in patients with type 2 diabetes receiving TOUJEO ranged from 8% to 37% at 26 weeks and the highest risk was again seen in patients receiving TOUJEO as part of a multiple daily injection regimen. Insulin Initiation and Intensification of Glucose Control Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy. Peripheral Edema Insulin, including TOUJEO, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy Long-term use of insulin, including TOUJEO, can cause lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients and may affect insulin absorption [see Dosage and Administration (2.1)]. Weight Gain Weight gain has occurred with some insulin therapies including TOUJEO and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Allergic Reactions Some patients taking insulin therapy, including TOUJEO have 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 [see Warnings and Precautions (5.5)]. Cardiovascular Safety No clinical studies to establish the cardiovascular safety of TOUJEO have been conducted. A cardiovascular outcomes trial, ORIGIN, has been conducted with LANTUS. It is unknown whether the results of ORIGIN can be applied to TOUJEO. 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 a 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. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. In a 6-month study of type 1 diabetes patients, 79% of patients who received TOUJEO 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 TOUJEO with antibody test at baseline remained AIA positive at month 6. In two 6-month studies in type 2 diabetes patients, 25% of patients who received TOUJEO 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 TOUJEO 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 TOUJEO with the incidence of antibodies in other studies or to other products may be misleading.