FDA label de2fb09f-2569-4360-bf2c-65bc515ab6be

5 WARNINGS AND PRECAUTIONS Anaphylaxis and Serious Hypersensitivity Reactions: Discontinue ADLYXIN and promptly seek medical advice. ( 5.1 ) Pancreatitis: Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis. ( 5.2 ) Never share ADLYXIN pen between patients, even if the needle is changed. ( 5.3 ) Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin: Patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. Reduction in the dose of insulin secretagogues or insulin may be necessary. ( 5.4 ) Acute Kidney Injury: Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions. ADLYXIN is not recommended in patients with end stage renal disease. ( 5.5 ) Immunogenicity: Patients may develop antibodies to lixisenatide. If there is worsening glycemic control or failure to achieve targeted glycemic control, significant injection site reactions or allergic reactions, alternative antidiabetic therapy should be considered. ( 5.6 ) Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.7 ) 5.1 Anaphylaxis and Serious Hypersensitivity Reactions In clinical trials of ADLYXIN, there have been cases of anaphylaxis determined to be related to ADLYXIN (frequency of 0.1% or 10 cases per 10,000 patient-years). Other serious hypersensitivity reactions including angioedema also occurred [see Adverse Reactions (6.1) ] . Inform and closely monitor patients with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist for allergic reactions, because it is unknown whether such patients will be predisposed to anaphylaxis with ADLYXIN. ADLYXIN is contraindicated in patients with known hypersensitivity to lixisenatide [see Contraindications (4) ] . If a hypersensitivity reaction occurs, the patient should discontinue ADLYXIN and promptly seek medical attention. 5.2 Pancreatitis Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been reported postmarketing in patients treated with GLP-1 receptor agonists. In clinical trials of ADLYXIN, there were 21 cases of pancreatitis among ADLYXIN-treated patients and 14 cases in comparator-treated patients (incidence rate of 21 vs. 17 per 10,000 patient-years). ADLYXIN cases were reported as acute pancreatitis (n=3), pancreatitis (n=12), chronic pancreatitis (n=5), and edematous pancreatitis (n=1). Some patients had risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse. After initiation of ADLYXIN, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, promptly discontinue ADLYXIN and initiate appropriate management. If pancreatitis is confirmed, do not restart ADLYXIN. Consider antidiabetic therapies other than ADLYXIN in patients with a history of pancreatitis. 5.3 Never Share ADLYXIN Pen Between Patients ADLYXIN pens should never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens. 5.4 Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin Patients receiving ADLYXIN in combination with basal insulin or insulin secretagogue (e.g., sulfonylurea) have an increased risk of hypoglycemia, including severe hypoglycemia. In patients receiving sulfonylurea with or without metformin, 14.5% patients on ADLYXIN reported symptomatic hypoglycemia compared to 10.6% for those on placebo. In patients receiving basal insulin with or without metformin, 28.3% patients on ADLYXIN reported symptomatic hypoglycemia compared to 23.0% for those on placebo. In patients receiving basal insulin with sulfonylurea, 47.2% patients on ADLYXIN reported symptomatic hypoglycemia compared to 21.6% for those on placebo [see Adverse Reactions (6.1) ] . The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin. Inform patients using these concomitant medications of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia [see Drug Interactions (7.2) ] . 5.5 Acute Kidney Injury Acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis has been reported postmarketing in patients treated with ADLYXIN. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function when initiating or escalating doses of ADLYXIN in patients with renal impairment and in patients reporting severe gastrointestinal reactions. ADLYXIN is not recommended in patients with end stage renal disease [see Use in Specific Populations (8.6) ] . 5.6 Immunogenicity Patients may develop antibodies to lixisenatide following treatment with ADLYXIN. A pooled analysis of studies of lixisenatide-treated patients showed that 70% were antibody positive at Week 24. In the subset of patients (2.4 %) with the highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed. A higher incidence of allergic reactions and injection site reactions occurred in antibody positive patients [see Warnings and Precautions (5.1) , Adverse Reactions (6.2) ] . If there is worsening glycemic control or failure to achieve targeted glycemic control, significant injection site reactions or allergic reactions, alternative antidiabetic therapy should be considered [see Adverse Reactions (6.1) ] . 5.7 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In the ELIXA study [see Clinical Studies (14.6) ] , cholelithiasis occurred in 0.4% of ADLYXIN-treated patients versus 0.2% in placebo-treated patients and acute cholecystitis in 0.3% of ADLYXIN-treated patients versus 0.2% in placebo-treated patients. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

6 ADVERSE REACTIONS The following serious reactions are described below or elsewhere in the prescribing information: Anaphylaxis and Serious Hypersensitivity Reactions [see Warnings and Precautions (5.1) ] Pancreatitis [see Warnings and Precautions (5.2) ] Hypoglycemia with Concomitant Use of Insulin Secretagogues or Insulin [see Warnings and Precautions (5.4) ] Renal Failure [see Warnings and Precautions (5.5) ] Immunogenicity [see Warnings and Precautions (5.6) ] Acute Gallbladder Disease [see Warnings and Precautions 5.7) ] The most common adverse reactions (≥5%) of patients treated with ADLYXIN are nausea, vomiting, headache, diarrhea, dizziness, and hypoglycemia. ( 6.1 ) 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 observed in practice. Pool of Placebo-Controlled Trials The data in Table 1 are derived from the placebo-controlled trials [see Clinical Studies (14) ] . These data reflect exposure of 2869 patients to ADLYXIN and a mean duration of exposure to ADLYXIN of 21.7 weeks. Across the treatment arms, the mean age of patients was 56.1 years, 2.3% were 75 years or older and 48.2% were male. The population in these studies was 63.7% White, 2.6% Black or African American, 32.0% Asian, and 18.9% were of Hispanic or Latino ethnicity. At baseline, the population had diabetes for an average of 8.2 years and had a mean HbA1c of 8.1%. At baseline, 11.2% of the population reported retinopathy. Baseline estimated renal function was normal or mildly impaired (eGFR ≥60 mL/min/1.73 m 2 ) in 95.3% of the pooled study populations. Table 1 shows common adverse reactions, excluding hypoglycemia, associated with the use of ADLYXIN in the pool of placebo-controlled trials. These adverse reactions were not present at baseline, occurred more commonly on ADLYXIN than on placebo, and occurred in at least 5% of patients treated with ADLYXIN. Table 1: Adverse Reactions Reported in ≥5% of ADLYXIN-Treated Patients with Type 2 Diabetes Mellitus and Occurring More Frequently Compared to Placebo Adverse Reaction Placebo (N=1639) ADLYXIN (N=2869) * hypoglycemia is discussed separately. Nausea 6% 25% Vomiting 2% 10% Headache 6% 9% Diarrhea 6% 8% Dizziness 4% 7% Gastrointestinal adverse reactions In the pool of placebo-controlled trials, gastrointestinal adverse reactions occurred more frequently among patients receiving ADLYXIN than placebo (placebo 18.4%, ADLYXIN 39.7%). More patients receiving ADLYXIN (4.3%) discontinued treatment due to gastrointestinal adverse reactions than patients receiving placebo (0.5%). Investigators graded the severity of gastrointestinal adverse reactions occurring on ADLYXIN as "mild" in 64.2% of cases, "moderate" in 32.3% of cases, or "severe" in 3.5% of cases. The majority of these adverse reactions occurred during the first 3 weeks after starting treatment. In addition to the reactions in Table 1, the following adverse reactions were reported in >2% of patients and more frequently in ADLYXIN-treated patients than placebo (frequencies listed, respectively, as: placebo; ADLYXIN): dyspepsia (0.2%, 3.2%), constipation (1.8%, 2.8%), abdominal distension (0.9%, 2.2%), abdominal pain upper (0.9%, 2.2%), abdominal pain (1.5%, 2.0%). Hypoglycemia Symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from a hypoglycemic episode with an accompanying plasma glucose <60 mg/dL or associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose value was available. Severe symptomatic hypoglycemia was defined as an event with clinical symptoms that were considered to result from hypoglycemia in which the patient required the assistance of another person, associated with a plasma glucose level below 36 mg/dL or, associated with prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration if no plasma glucose was available. Table 2 summarizes the incidence of symptomatic hypoglycemia and severe hypoglycemia in seven placebo-controlled efficacy/safety studies. Table 2: Incidence (%) of Symptomatic Hypoglycemia and Severe Hypoglycemia in Patients with Type 2 Diabetes Mellitus during the 24-week Main Treatment Period Background Therapy Placebo ADLYXIN Monotherapy 12-week treatment duration. N=122 N=239 Symptomatic (%) 2 2 Severe (%) 0 0 With Metformin N=432 N=946 Symptomatic (%) 1 3 Severe (%) 0 0 With Sulfonylurea +/- metformin N=377 N=656 Symptomatic (%) 11 15 Severe (%) 0 0.2 With Pioglitazone +/- metformin N=161 N=323 Symptomatic (%) 1 3 Severe (%) 0 0 With Basal insulin +/- metformin N=213 N=374 Symptomatic (%) 23 28 Severe (%) 0 1 With Basal insulin +/- sulfonylurea N=111 N=108 Symptomatic (%) 22 47 Severe (%) 0 0 With Insulin Glargine and metformin +/- thiazolidinedione N=223 N=223 Symptomatic (%) 14 22 Severe (%) 0 0.4 Injection site reactions Injections site reactions (e.g., pain, pruritus, and erythema) were reported more frequently in ADLYXIN-treated patients (4%) than placebo treated patients (2%). Anaphylaxis and hypersensitivity In the ADLYXIN development program anaphylaxis cases were adjudicated. Anaphylaxis was defined as a skin or mucosal lesion of acute onset associated with at least 1 other organ system involvement. Symptoms such as hypotension, laryngeal edema or severe bronchospasm could be present but were not required for the case definition. More cases adjudicated as meeting the definition for anaphylaxis occurred in ADLYXIN-treated patients (incidence rate of 0.2% or 16 cases per 10,000 patient years) than placebo treated patient (incidence rate of 0.1% or 7 cases per 10,000 patient years). Allergic reactions (such as anaphylactic reaction, angioedema and urticaria) adjudicated as possibly related to the study medication were observed more frequently in ADLYXIN-treated patients (0.4%) than placebo-treated patient (0.2%). Acute Gallbladder Disease In the ELIXA study [see Clinical Studies (14.6) ] , cholelithiasis occurred in 0.4% of ADLYXIN-treated patients versus 0.2% in placebo-treated patients and acute cholecystitis in 0.3% of ADLYXIN-treated patients versus 0.2% in placebo-treated patients. 6.2 Immunogenicity In the pool of 9 placebo-controlled studies, 70% of patients exposed to lixisenatide tested positive for anti-lixisenatide antibodies during the trials. In the subset of patients (2.4%) with the highest antibody concentrations (>100 nmol/L), an attenuated glycemic response was observed. A higher incidence of allergic reactions and injection site reactions occurred in antibody positive patients [see Warnings and Precautions (5.6) ] . Anti-lixisenatide antibody characterization studies have demonstrated the potential for development of antibodies cross-reactive with endogenous GLP-1 and glucagon, but the clinical significance of these antibodies is not currently known. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, the incidence of antibodies to lixisenatide cannot be directly compared with the incidence of antibodies with other products. 6.3 Post-Marketing Experience The following additional adverse reactions have been reported during post-approval use of ADLYXIN. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hepatobiliary: cholecystitis, cholelithiasis requiring cholecystectomy Gastrointestinal: ileus Nervous system: dysgeusia

<table width="65%" ID="table1"><caption>Table 1: Adverse Reactions Reported in &#x2265;5% of ADLYXIN-Treated Patients with Type 2 Diabetes Mellitus and Occurring More Frequently Compared to Placebo </caption><col width="40%" align="left" valign="middle"/><col width="30%" align="center" valign="middle"/><col width="30%" align="center" valign="middle"/><thead><tr><th valign="bottom" styleCode="Lrule Rrule">Adverse Reaction</th><th align="center" styleCode="Rrule">Placebo (N=1639)</th><th align="center" styleCode="Rrule">ADLYXIN (N=2869)</th></tr></thead><tfoot><tr><td align="left" colspan="3" valign="top">* hypoglycemia is discussed separately.</td></tr></tfoot><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">25%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">10%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">9%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diarrhea</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">8%</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">7%</td></tr></tbody></table>

<table width="75%" ID="table2"><caption>Table 2: Incidence (%) of Symptomatic Hypoglycemia and Severe Hypoglycemia in Patients with Type 2 Diabetes Mellitus during the 24-week Main Treatment Period </caption><col width="50%" align="left" valign="top"/><col width="25%" align="center" valign="top"/><col width="25%" align="center" valign="top"/><thead><tr><th styleCode="Lrule" valign="middle">Background Therapy</th><th styleCode="Lrule" valign="middle">Placebo</th><th styleCode="Lrule Rrule" valign="middle">ADLYXIN</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">Monotherapy<footnote>12-week treatment duration.</footnote></content></td><td styleCode="Rrule"><content styleCode="bold">N=122</content></td><td styleCode="Rrule"><content styleCode="bold">N=239</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Symptomatic (%)</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">With Metformin</content></td><td styleCode="Rrule"><content styleCode="bold">N=432</content></td><td styleCode="Rrule"><content styleCode="bold">N=946</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Symptomatic (%)</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">With Sulfonylurea +/- metformin</content></td><td styleCode="Rrule"><content styleCode="bold">N=377</content></td><td styleCode="Rrule"><content styleCode="bold">N=656</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Symptomatic (%)</td><td styleCode="Rrule">11</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0.2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">With Pioglitazone +/- metformin</content></td><td styleCode="Rrule"><content styleCode="bold">N=161</content></td><td styleCode="Rrule"><content styleCode="bold">N=323</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Symptomatic (%)</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">With Basal insulin +/- metformin</content></td><td styleCode="Rrule"><content styleCode="bold">N=213</content></td><td styleCode="Rrule"><content styleCode="bold">N=374</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Symptomatic (%)</td><td styleCode="Rrule">23</td><td styleCode="Rrule">28</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"><content styleCode="bold">With Basal insulin +/- sulfonylurea</content></td><td styleCode="Rrule"><content styleCode="bold">N=111</content></td><td styleCode="Rrule"><content styleCode="bold">N=108</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Symptomatic (%)</td><td styleCode="Rrule">22</td><td styleCode="Rrule">47</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" align="left"><content styleCode="bold">With Insulin Glargine and metformin +/- thiazolidinedione</content></td><td styleCode="Rrule"><content styleCode="bold">N=223</content></td><td styleCode="Rrule"><content styleCode="bold">N=223</content></td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Symptomatic (%)</td><td styleCode="Rrule">14</td><td styleCode="Rrule">22</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Severe (%)</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0.4</td></tr></tbody></table>