them with a meal or snack when adlyxin is not administered. oral medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen, should be administered at least 1 hour before adlyxin injection [see clinical pharmacology (12.3) ] . patients taking oral contraceptives should be advised to take them at least 1 hour before adlyxin administration or at least 11 hours after the dose of adlyxin [see clinical pharmacology (12.3) ] . 7.2 dosage adjustment of sulfonylurea or insulin with concomitant use with adlyxin when initiating adlyxin, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see warnings and precautions (5.4) and adverse reactions (6.1) ] .

litus. adlyxin has not been studied in patients with gastroparesis and is not recommended in patients with gastroparesis.

ycemic 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.

injection of adlyxin within one hour before the first meal of the day preferably the same meal each day. if a dose is missed, administer adlyxin within one hour prior to the next meal.

ectly 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

them with a meal or snack when adlyxin is not administered. oral medications that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, or medications for which a delay in effect is undesirable, such as acetaminophen, should be administered at least 1 hour before adlyxin injection [see clinical pharmacology (12.3) ] . patients taking oral contraceptives should be advised to take them at least 1 hour before adlyxin administration or at least 11 hours after the dose of adlyxin [see clinical pharmacology (12.3) ] . 7.2 dosage adjustment of sulfonylurea or insulin with concomitant use with adlyxin when initiating adlyxin, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see warnings and precautions (5.4) and adverse reactions (6.1) ] .

se, respectively, based on plasma auc [see data ] . the estimated background risk of major birth defects is 6–10% in women with pregestational diabetes with a hba1c >7 and has been reported to be as high as 20%–25% in women with a hba1c >10. the estimated background risk of miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. data animal data in pregnant rats receiving twice daily subcutaneous doses of 2.5, 35, or 500 mcg/kg during organogenesis (gestation day 6 to 17), fetuses were present with visceral closure defects (e.g., microphthalmia, bilateral anophthalmia, diaphragmatic hernia) and stunted growth. impaired ossification associated with skeletal malformations (e.g., bent limbs, scapula, clavicle, and pelvis) were observed at ≥5 mcg/kg/day, resulting in systemic exposure that is 1-time the 20 mcg/day clinical dose, based on plasma auc. decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the adverse fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. placental transfer of lixisenatide to developing rat fetuses is low with a concentration ratio in fetal/maternal plasma of 0.1%. in pregnant rabbits receiving twice daily subcutaneous doses of 2.5, 25, 250 mcg/kg during organogenesis (gestation day 6 to 18), fetuses were present with multiple visceral and skeletal malformations, including closure defects, at ≥5 mcg/kg/day or systemic exposures that are 6-times the 20 mcg/day clinical dose, based on plasma auc. decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. placental transfer of lixisenatide to developing rabbit fetuses is low with a concentration ratio in fetal/maternal plasma of ≤0.3%. in a second study in pregnant rabbits, no drug-related malformations were observed from twice daily subcutaneous doses of 0.15, 1.0, and 2.5 mcg/kg administered during organogenesis, resulting in systemic exposures up to 9-times the clinical exposure at 20 mcg/day, based on plasma auc. in pregnant rats given twice daily subcutaneous doses of 2, 20, or 200 mcg/kg from gestation day 6 through lactation, decreases in maternal body weight, food consumption, motor activity were observed at all doses. skeletal malformations and increased pup mortality were observed at 400 mcg/kg/day, which is approximately 200-times the 20 mcg/day clinical dose, based on mcg/m 2 . 8.2 lactation risk summary there is no information regarding the presence of adlyxin in human milk, the effects on the breastfed infant, or the effects on milk production. however, lixisenatide is present in rat milk [see data ] . the developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for lixisenatide and any potential adverse effects on the breastfed infant from lixisenatide or from the underlying maternal condition. data animal data a study in lactating rats showed low (9.4%) transfer of lixisenatide and its metabolites into milk and negligible (0.01%) levels of unchanged lixisenatide protein in the gastric contents of weaning offspring. 8.4 pediatric use safety and effectiveness of adlyxin have not been established in pediatric patients. 8.5 geriatric use in clinical studies of adlyxin, a total of 1837 (25%) of the patients exposed to the study medication were 65 years of age and over and 288 (4%) were 75 years of age and over. no overall differences were observed in safety or effectiveness between these patients and younger patients, but individual sensitivity cannot be ruled out. 8.6 renal impairment in patients with mild renal impairment (egfr: 60–89 ml/min/1.73 m 2 ) no dose adjustment is required [see clinical pharmacology (12.3) ] but close monitoring for adlyxin related adverse reactions [see adverse reactions (6.1) ] and for changes in renal function is recommended because a higher incidence of hypoglycemia, nausea and vomiting were observed in these patients. in a cardiovascular outcome study, 655 (22%) lixisenatide treated patients had moderate renal impairment (egfr: 30 to less than 60 ml/min/1.73 m 2 ). no dosing adjustment is recommended in patients with moderate renal impairment [see clinical pharmacology (12.3) ] but close monitoring for adlyxin related adverse gastrointestinal reactions [see adverse reactions (6.1) ] and for changes in renal function is recommended because these may lead to dehydration and acute renal failure and worsening of chronic failure in these patients [see warnings and precautions (5.5) ] . clinical experience in patients with severe renal impairment is limited as there were only 5 patients with severe renal impairment (egfr 15 to less than 30 ml/min/1.73 m 2 ) exposed to adlyxin in all controlled studies. lixisenatide exposure was higher in these patients [see clinical pharmacology (12.3) ] . patients with severe renal impairment exposed to adlyxin should be closely monitored for occurrence of gastrointestinal adverse reactions and for changes in renal function [see warnings and precautions (5.5) ] . there is no therapeutic experience in patients with end stage renal disease (egfr <15 ml/min/1.73 m 2 ), and it is not recommended to use adlyxin in this population [see clinical pharmacology (12.3) ] . 8.7 patients with gastroparesis adlyxin slows gastric emptying. patients with preexisting gastroparesis were excluded from clinical trials of adlyxin. adlyxin should not be initiated in patients with severe gastroparesis.

a hba1c >7 and has been reported to be as high as 20%–25% in women with a hba1c >10. the estimated background risk of miscarriage for the indicated population is unknown. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risk poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity. data animal data in pregnant rats receiving twice daily subcutaneous doses of 2.5, 35, or 500 mcg/kg during organogenesis (gestation day 6 to 17), fetuses were present with visceral closure defects (e.g., microphthalmia, bilateral anophthalmia, diaphragmatic hernia) and stunted growth. impaired ossification associated with skeletal malformations (e.g., bent limbs, scapula, clavicle, and pelvis) were observed at ≥5 mcg/kg/day, resulting in systemic exposure that is 1-time the 20 mcg/day clinical dose, based on plasma auc. decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the adverse fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. placental transfer of lixisenatide to developing rat fetuses is low with a concentration ratio in fetal/maternal plasma of 0.1%. in pregnant rabbits receiving twice daily subcutaneous doses of 2.5, 25, 250 mcg/kg during organogenesis (gestation day 6 to 18), fetuses were present with multiple visceral and skeletal malformations, including closure defects, at ≥5 mcg/kg/day or systemic exposures that are 6-times the 20 mcg/day clinical dose, based on plasma auc. decreases in maternal body weight, food consumption, and motor activity were observed concurrent with the fetal findings, which confounds the interpretation of relevance of these malformations to the human risk assessment. placental transfer of lixisenatide to developing rabbit fetuses is low with a concentration ratio in fetal/maternal plasma of ≤0.3%. in a second study in pregnant rabbits, no drug-related malformations were observed from twice daily subcutaneous doses of 0.15, 1.0, and 2.5 mcg/kg administered during organogenesis, resulting in systemic exposures up to 9-times the clinical exposure at 20 mcg/day, based on plasma auc. in pregnant rats given twice daily subcutaneous doses of 2, 20, or 200 mcg/kg from gestation day 6 through lactation, decreases in maternal body weight, food consumption, motor activity were observed at all doses. skeletal malformations and increased pup mortality were observed at 400 mcg/kg/day, which is approximately 200-times the 20 mcg/day clinical dose, based on mcg/m 2 .

relevant extent. heart rate no increase in mean heart rate was seen in placebo-controlled studies. 12.3 pharmacokinetics absorption following subcutaneous administration in patients with type 2 diabetes, the median t max is 1 to 3.5 hours. there are no clinically relevant differences in the rate of absorption when lixisenatide is administered subcutaneously in the abdomen, thigh, or arm. distribution the apparent volume of distribution after subcutaneous administration of lixisenatide (vz/f) is approximately 100 l. elimination metabolism and elimination lixisenatide is presumed to be eliminated through glomerular filtration, and proteolytic degradation. after multiple dose administration in patients with type 2 diabetes, mean terminal half-life was approximately 3 hours and the mean apparent clearance (cl/f) about 35 l/h. specific populations effects of age, body weight, gender, and race age, body weight, gender, and race were not observed to meaningfully affect the pharmacokinetics of lixisenatide in population pk analyses [see use in specific populations (8.5) ] . renal impairment compared to healthy subjects (creatinine clearance using cockcroft-gault [clcr] greater than or equal to 90 ml/min [n=4]), plasma c max of lixisenatide was increased by approximately 60%, 42%, and 83% in patients with mild (clcr 60–89 ml/min [n=9]), moderate (clcr 30–59 ml/min [n=11]), and severe (clcr 15–29 ml/min [n=8]) renal impairment. plasma auc was increased by approximately 34%, 69%, and 124% with mild, moderate, and severe renal impairment, respectively [see use in specific populations (8.6) ] . hepatic impairment no pharmacokinetic study has been performed in patients with acute or chronic hepatic impairment. hepatic dysfunction is not expected to affect the pharmacokinetics of lixisenatide. drug interaction studies acetaminophen adlyxin 10 mcg did not change the overall exposure (auc) of acetaminophen following administration of a single dose of acetaminophen 1000 mg, whether before or after adlyxin. no effects on acetaminophen c max and t max were observed when acetaminophen was administered 1 hour before adlyxin. when administered 1 or 4 hours after 10 mcg of adlyxin, c max of acetaminophen was decreased by 29% and 31%, respectively, and median t max was delayed by 2.0 and 1.75 hours, respectively. oral contraceptives administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour before or 11 hours after 10 mcg of adlyxin, did not change c max , auc, t 1/2 and t max of ethinylestradiol and levonorgestrel. administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour or 4 hours after 10 mcg of adlyxin did not affect the overall exposure (auc) and mean terminal half-life (t 1/2 ) of ethinylestradiol and levonorgestrel. however, c max of ethinylestradiol was decreased by 52% and 39%, respectively, and c max of levonorgestrel was decreased by 46% and 20%, respectively, and median t max was delayed by 1 to 3 hours [see drug interactions (7.1) ] . atorvastatin when adlyxin 20 mcg and atorvastatin 40 mg were coadministered in the morning for 6 days, the overall exposure (auc) of atorvastatin was not affected, while c max was decreased by 31% and t max was delayed by 3.25 hours. no such increase for t max was observed when atorvastatin was administered in the evening and adlyxin in the morning but the auc and c max of atorvastatin were increased by 27% and 66%, respectively. warfarin and other coumarin derivatives after concomitant administration of warfarin 25 mg with repeated dosing of adlyxin 20 mcg, there were no effects on auc or inr (international normalized ratio) while c max was reduced by 19% and t max was delayed by 7 hours [see drug interactions (7.1) ] . digoxin after concomitant administration of adlyxin 20 mcg and digoxin 0.25 mg at steady state, the auc of digoxin was not affected. the t max of digoxin was delayed by 1.5 hour and the c max was reduced by 26% [see drug interactions (7.1) ] . ramipril after concomitant administration of adlyxin 20 mcg and ramipril 5 mg during 6 days, the auc of ramipril was increased by 21% while the c max was decreased by 63%. the auc and c max of the active metabolite (ramiprilat) were not affected. the t max of ramipril and ramiprilat were delayed by approximately 2.5 hours.

compared to healthy subjects (creatinine clearance using cockcroft-gault [clcr] greater than or equal to 90 ml/min [n=4]), plasma c max of lixisenatide was increased by approximately 60%, 42%, and 83% in patients with mild (clcr 60–89 ml/min [n=9]), moderate (clcr 30–59 ml/min [n=11]), and severe (clcr 15–29 ml/min [n=8]) renal impairment. plasma auc was increased by approximately 34%, 69%, and 124% with mild, moderate, and severe renal impairment, respectively [see use in specific populations (8.6) ] . hepatic impairment no pharmacokinetic study has been performed in patients with acute or chronic hepatic impairment. hepatic dysfunction is not expected to affect the pharmacokinetics of lixisenatide. drug interaction studies acetaminophen adlyxin 10 mcg did not change the overall exposure (auc) of acetaminophen following administration of a single dose of acetaminophen 1000 mg, whether before or after adlyxin. no effects on acetaminophen c max and t max were observed when acetaminophen was administered 1 hour before adlyxin. when administered 1 or 4 hours after 10 mcg of adlyxin, c max of acetaminophen was decreased by 29% and 31%, respectively, and median t max was delayed by 2.0 and 1.75 hours, respectively. oral contraceptives administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour before or 11 hours after 10 mcg of adlyxin, did not change c max , auc, t 1/2 and t max of ethinylestradiol and levonorgestrel. administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour or 4 hours after 10 mcg of adlyxin did not affect the overall exposure (auc) and mean terminal half-life (t 1/2 ) of ethinylestradiol and levonorgestrel. however, c max of ethinylestradiol was decreased by 52% and 39%, respectively, and c max of levonorgestrel was decreased by 46% and 20%, respectively, and median t max was delayed by 1 to 3 hours [see drug interactions (7.1) ] . atorvastatin when adlyxin 20 mcg and atorvastatin 40 mg were coadministered in the morning for 6 days, the overall exposure (auc) of atorvastatin was not affected, while c max was decreased by 31% and t max was delayed by 3.25 hours. no such increase for t max was observed when atorvastatin was administered in the evening and adlyxin in the morning but the auc and c max of atorvastatin were increased by 27% and 66%, respectively. warfarin and other coumarin derivatives after concomitant administration of warfarin 25 mg with repeated dosing of adlyxin 20 mcg, there were no effects on auc or inr (international normalized ratio) while c max was reduced by 19% and t max was delayed by 7 hours [see drug interactions (7.1) ] . digoxin after concomitant administration of adlyxin 20 mcg and digoxin 0.25 mg at steady state, the auc of digoxin was not affected. the t max of digoxin was delayed by 1.5 hour and the c max was reduced by 26% [see drug interactions (7.1) ] . ramipril after concomitant administration of adlyxin 20 mcg and ramipril 5 mg during 6 days, the auc of ramipril was increased by 21% while the c max was decreased by 63%. the auc and c max of the active metabolite (ramiprilat) were not affected. the t max of ramipril and ramiprilat were delayed by approximately 2.5 hours.

xicity tests (bacterial mutagenicity (ames), human lymphocyte chromosome aberration, mouse bone marrow micronucleus). impairment of fertility studies in which male and female rats received twice daily subcutaneous doses of 2, 29, or 414 mcg/kg/dose prior to pairing through gestation day 6 did not indicate any adverse effects on male or female fertility in rats up to the highest dose tested, 414 mcg/kg/dose, which is approximately 400-times the clinical dose at 20 mcg/day based on mcg/m 2 .

tagenicity (ames), human lymphocyte chromosome aberration, mouse bone marrow micronucleus). impairment of fertility studies in which male and female rats received twice daily subcutaneous doses of 2, 29, or 414 mcg/kg/dose prior to pairing through gestation day 6 did not indicate any adverse effects on male or female fertility in rats up to the highest dose tested, 414 mcg/kg/dose, which is approximately 400-times the clinical dose at 20 mcg/day based on mcg/m 2 .

ek 12 (see table 3 ). the adjusted mean change in weight from baseline did not differ significantly between adlyxin (-1.9 kg) and placebo (-2.0 kg). table 3: placebo-controlled study (12-week treatment period results) – intent-to-treat (itt) population placebo (n=122) adlyxin 20 mcg (n=119) itt population = all randomized patients. 10% of patients in adlyxin and 10% in the placebo had missing hba1c data at week 12 in the itt population. hba 1c (%) baseline (mean) 8.07 8.07 ls mean change from baseline using multiple imputation with respect to jump to placebo for missing data at week 12 in the adlyxin group. -0.18 -0.83 difference from placebo (95% ci) -0.65 (-0.903, -0.399) (p<0.0001) patients (%) achieving hba 1c <7.0% patients with missing hba1c value at week 12 were considered nonresponders. 24 44 fasting plasma glucose (fpg) (mg/dl) baseline (mean) 160.39 162.77 ls mean change from baseline 1.46 -15.84 body weight (kg) baseline (mean) 86.08 86.50 ls mean change from baseline -2.03 -1.94 14.2 add-on combination therapy to metformin (alone or in combination with sulfonylurea) in a 24-week study, 323 patients with type 2 diabetes inadequately controlled on diet, exercise, and metformin were randomized to adlyxin 20 mcg once daily or placebo. the mean age of the study population was 56.7 years, and the mean duration of type 2 diabetes mellitus was 5.9 years; 44.6% were male, 90.1% were white, 0.6% were black or african american, 27.9% were hispanic, and 1.2% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 33 kg/m 2 . the mean dose of metformin was 1955 mg per day. compared with placebo, treatment with adlyxin 20 mcg once daily resulted in statistically significant reductions in hba1c from baseline at week 24 (see table 4 ). table 4: placebo-controlled study in patients with type 2 diabetes mellitus in combination with metformin (24-week results) – itt population background therapy with metformin 11% of patients in adlyxin 20 mcg and 6% in the placebo had missing hba1c data at week 24 in the itt population. placebo (n=162) adlyxin 20 mcg (n=161) itt population = all randomized patients. hba 1c (%) baseline (mean) 8.03 7.99 ls mean change from baseline using multiple imputation with respect to jump to placebo for missing data at week 24 in the adlyxin group. -0.26 -0.72 difference from placebo (95% ci) -0.46 (-0.640, -0.279) (p<0.0001) patients (%) achieving hba 1c <7.0% patients with missing hba1c value at week 24 were considered nonresponders. 22 44 fasting plasma glucose (fpg) (mg/dl) baseline (mean) 170.32 172.23 ls mean change from baseline -7.25 -16.88 difference from placebo (95% ci) -9.64 (-16.306, -2.970) (p=0.0046) body weight (kg) baseline (mean) 87.87 90.21 ls mean change from baseline -1.71 -2.70 difference from placebo (95% ci) -1.00 (-1.706, -0.286) (p=0.006) in a 24-week study, 391 asian patients with type 2 diabetes inadequately controlled on diet, exercise, and metformin with or without a sulfonylurea were randomized to adlyxin 20 mcg once daily or placebo. the mean age of the study population was 54.8 years, and mean duration of type 2 diabetes mellitus was 6.6 years. 49.1% were male. all patients were asian. 2.8% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 27 kg/m 2 . the mean dose of metformin was 1368 mg per day and 44.8% of patients were on a sulfonylurea. compared with placebo, treatment with adlyxin 20 mcg once daily resulted in statistically significant reductions in hba1c from baseline at week 24 (see table 5 ). table 5: placebo-controlled study in asian patients with type 2 diabetes mellitus in combination with metformin with or without sulfonylurea (24-week results) – itt population background therapy with metformin +/- sulfonylurea 7% of patients in adlyxin and 6% in the placebo had missing hba1c data at week 24 in the itt population. placebo (n=195) adlyxin 20 mcg (n=196) itt population = all randomized patients. hba 1c (%) baseline (mean) 7.85 7.95 ls mean change from baseline using multiple imputation with respect to jump to placebo for missing data at week 24 in the adlyxin group. -0.57 -0.84 difference from placebo (95% ci) -0.27 (-0.447, -0.090) (p=0.0032) patients (%) achieving hba 1c <7.0% patients with missing hba1c value at week 24 were considered nonresponders. 37 49 fasting plasma glucose (fpg) (mg/dl) baseline (mean) 157.47 159.26 ls mean change from baseline -7.05 -13.39 body weight (kg) baseline (mean) 72.74 73.18 ls mean change from baseline -1.12 -1.36 in a 24-week open-label study, 634 patients with type 2 diabetes inadequately controlled on diet, exercise and metformin were randomized to adlyxin 20 mcg once daily or exenatide 10 mcg twice daily. the mean age of the study population was 57.4 years, and mean duration of type 2 diabetes mellitus was 6.8 year; 53.3% were male, 92.7% were white, 2.8% were black or african american, 26.8% were hispanic, and 1.7% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 34 kg/m 2 . the mean dose of metformin was 2039 mg per day. adlyxin 20 mcg once daily met the prespecified noninferiority margin of 0.4% versus exenatide 10 mg bid for the difference in hba1c reduction from baseline (see table 6 ). however in this study, adlyxin provided less hba1c reduction than exenatide 10 mg bid and the difference was statistically significant (p=0.0175). table 6: active-controlled study in patients with type 2 diabetes mellitus in combination with metformin (24-week treatment period results) – itt population adlyxin (n=318) exenatide bid (n=316) itt population = all randomized patients. 14% of patients in adlyxin and 14% in exenatide had missing hba1c data at week 24 in the itt population. hba1c (%) baseline (mean) 7.95 7.97 ls mean change from baseline using multiple imputation with respect to use the baseline value for missing data at week 24 in each group. -0.73 -0.90 ls mean difference vs exenatide bid 0.17 95% ci (0.030 to 0.314) (p=0.0175) patients (%) achieving hba 1c <7.0% patients with missing hba1c value at week 24 were considered nonresponders. 43.1 45.6 fasting plasma glucose (fpg) (mg/dl) baseline 174.24 173.88 ls mean change from baseline -19.79 -24.19 body weight (kg) baseline 94.01 96.09 ls mean change from baseline -2.74 -3.72 14.3 add-on combination therapy to a sulfonylurea (alone or in combination with metformin) in a 24-week study, 859 patients with type 2 diabetes inadequately controlled with diet, exercise and a sulfonylurea with or without metformin were randomized to adlyxin 20 mcg once daily or placebo. the mean age of the study population was 57.2 years, and mean duration of type 2 diabetes mellitus was 9.3 years; 50.5% were male, 52.2% were white, 3.0% were black or african american, 2.7% were hispanic, and 4.7% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 30 kg/m 2 . the two most common sulfonylureas used were glimepiride and glibenclamide and the mean dose of these drugs at baseline were 5.1 mg and 12.9 mg, respectively, and 84.4% of patients were on metformin. compared with placebo, treatment with adlyxin 20 mcg once daily resulted in statistically significant reductions in hba1c from baseline at week 24 (see table 7 ). table 7: placebo-controlled study in patients with type 2 diabetes mellitus in combination with a sulfonylurea (24-week results) – itt population background therapy with sulfonylurea +/- metformin 13% of patients in adlyxin and 13% in the placebo had missing hba1c data at week 24 in the itt population. placebo (n=286) adlyxin 20 mcg (n=573) itt population = all randomized patients. hba 1c (%) baseline (mean) 8.21 8.28 ls mean change from baseline using multiple imputation with respect to jump to placebo for missing data at week 24 in the adlyxin group. -0.18 -0.77 difference from placebo (95% ci) -0.58 (-0.715, -0.453) (p<0.0001) patients (%) achieving hba 1c <7.0% patients with missing hba1c value at week 24 were considered nonresponders. 13 33 fasting plasma glucose (fpg) (mg/dl) baseline (mean) 167.47 174.24 ls mean change from baseline -10.36 -17.09 difference from placebo (95% ci) -6.73 (-11.946, -1.518) (p=0.0114) body weight (kg) baseline (mean) 84.34 82.34 ls mean change from baseline -0.83 -1.63 difference from placebo (95% ci) -0.80 (-1.244, -0.349) (p=0.0005) 14.4 add-on treatment to pioglitazone (alone or in combination with metformin) in a 24-week study, 484 patients with type 2 diabetes with inadequately controlled with diet, exercise and pioglitazone with or without metformin were randomized to adlyxin 20 mcg once daily or placebo. the mean age of the study population was 55.8 years, and mean duration of type 2 diabetes mellitus was 8.1 years; 52.5% were male, 83.7% were white, 4.8% were black or african american, 26.4% were hispanic, and 4.1% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 34 kg/m 2 . the mean dose of pioglitazone was 33.6 mg per day and 81.0% of patients were on metformin. compared with placebo, treatment with adlyxin 20 mcg once daily resulted in statistically significant reductions in hba1c from baseline at week 24 (see table 8 ). table 8: placebo-controlled study in patients with type 2 diabetes mellitus in combination with pioglitazone (24-week results) – itt population background therapy pioglitazone +/- metformin 9% of patients in adlyxin and 12% in the placebo had missing hba1c data at week 24 in the itt population. placebo (n=161) adlyxin 20 mcg (n=323) itt population = all randomized patients. hba 1c (%) baseline (mean) 8.06 8.08 ls mean change from baseline using multiple imputation with respect to jump to placebo for missing data at week 24 in the adlyxin group. -0.43 -0.91 difference from placebo (95% ci) -0.48 (-0.647, -0.318) (p<0.0001) patients (%) achieving hba 1c <7.0% patients with missing hba1c value at week 24 were considered nonresponders. 25 49 fasting plasma glucose (fpg) (mg/dl) baseline (mean) 164.49 164.16 ls mean change from baseline -14.12 -24.56 difference from placebo (95% ci) -10.45 (-16.580, -4.315) (p=0.0008) body weight (kg) baseline (mean) 96.74 92.93 ls mean change from baseline 0.26 -0.11 14.5 add-on to basal insulin (alone or in combination with oral antidiabetics) in a 24-week study, 496 patients with type 2 diabetes inadequately controlled on diet, exercise and basal insulin with or without metformin were randomized to adlyxin 20 mcg once daily or placebo. the mean age of the study population was 57.2 years, and mean duration of type 2 diabetes mellitus was 12.46 years; 46.0% were male, 77.6% were white, 4.0% were black or african american, 27.0% were hispanic, and 3.2% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 32 kg/m 2 . at baseline, the mean basal insulin dose was 54.9 units and 79.2% of individuals were receiving metformin. in another 24-week study, 311 asian patients with type 2 diabetes inadequately controlled on diet, exercise and basal insulin with or without a sulfonylurea were randomized to adlyxin 20 mcg once daily or to placebo. the mean age of the study population was 58.4 years, and mean duration of type 2 diabetes mellitus was 13.92 years; 47.9% were male, all patients were asian, and 15.8% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 25 kg/m 2 . at baseline, the mean basal insulin dose was 24.2 units and 70.4% of individuals were receiving a sulfonylurea. compared with placebo, treatment with adlyxin 20 mcg once daily resulted in statistically significant reductions in hba1c from baseline at week 24 (see table 9 ) in both studies. table 9: placebo-controlled studies in patients with type 2 diabetes mellitus in combination with a basal insulin (24-week treatment period results) – itt population background therapy with basal insulin +/- metformin 16% of patients in adlyxin and 13% in the placebo had missing hba1c data at week 24 with basal insulin +/- metformin in the itt population. with basal insulin +/- sulfonylurea conducted in an asian population. 8% of patients in adlyxin and 6% of patients in placebo had missing hba1c data at week 24 with basal insulin +/- sulfonylurea in the itt population. placebo (n=167) adlyxin 20 mcg (n=329) placebo (n=157) adlyxin 20 mcg (n=154) itt population = all randomized patients. hba 1c (%) baseline (mean) 8.37 8.42 8.52 8.54 ls mean change from baseline using multiple imputation with respect to jump to placebo for missing data at week 24 in the adlyxin group. -0.34 -0.71 0.07 -0.70 difference from placebo (95% ci) -0.36 (-0.557, -0.170) (p=0.0002) -0.76 (-1.005, -0.516) (p<0.0001) patients (%) achieving hba 1c <7.0% patients with missing hba1c value at week 24 were considered nonresponders. 11 25 6 33 fasting plasma glucose (fpg) (mg/dl) baseline (mean) 144.94 146.44 139.69 138.25 ls mean change from baseline -13.07 -13.02 2.02 -4.38 body weight (kg) baseline (mean) 88.94 87.10 65.60 65.93 ls mean change from baseline -0.36 -1.55 -0.03 -0.48 in a 24-week study, 446 patients with type 2 diabetes, inadequately controlled on diet exercise and on insulin glargine and metformin with or without thiazolidinediones, were randomized to adlyxin 20 mcg once daily or placebo. the mean age of the study population was 56.2 years, and mean duration of type 2 diabetes mellitus was 9.1 years; 49.8% were male, 74.4% were white, 4.5% were black or african american, 22.6% were hispanic, and 3.8% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 32 kg/m 2 . at baseline, the mean insulin glargine dose was 44.5 units, the mean metformin dose was 2049 mg and 12.1% of individuals were receiving thiazolidinedione. compared with placebo, treatment with adlyxin 20 mcg once daily resulted in statistically significant reductions in hba1c from baseline at week 24 (see table 10 ). table 10: placebo-controlled study in patients with type 2 diabetes mellitus in combination with insulin glargine (24-week results) – itt population background therapy with insulin glargine and metformin +/- thiazolidinediones 9% of patients in adlyxin and 5% in the placebo had missing hba1c data at week 24 in the itt population. placebo (n=223) adlyxin 20 mcg (n=223) itt population = all randomized patients. hba 1c (%) baseline (mean) 7.60 7.56 ls mean change from baseline using multiple imputation with respect to jump to placebo for missing data at week 24 in the adlyxin group. -0.42 -0.70 difference from placebo (95% ci) -0.28 (-0.434, -0.123) (p=0.0005) patients (%) achieving hba 1c <7.0% patients with missing hba1c value at week 24 were considered nonresponders. 39 50 fasting plasma glucose (fpg) (mg/dl) baseline (mean) 120.67 117.99 ls mean change from baseline 6.05 5.74 body weight (kg) baseline (mean) 86.75 87.31 ls mean change from baseline 1.09 0.31 difference from placebo (95% ci) -0.78 (-1.388, -0.168) (p=0.0125) in a 26-week open-label study, 894 patients with type 2 diabetes inadequately controlled on diet, exercise and basal insulin combined with 1 to 3 oral antidiabetic agents were randomized to adlyxin 20 mcg once daily or insulin glulisine once daily (qd) or insulin glulisine three times a day (tid) combined with insulin glargine with or without metformin. the mean age of the study population was 59.8 years, and mean duration of type 2 diabetes mellitus was 12.2 years; 45.3% were male, 92.6% were white, 4.0% were black or african american, 21.1% were hispanic, and 5.6% had an egfr <60 ml/min/1.73 m 2 . the mean bmi was 32 kg/m 2 . at baseline, the mean insulin glargine dose was 65.9 units and 87.4% of individuals were receiving metformin. adlyxin 20 mcg once daily met the prespecified noninferiority margin of 0.4% versus insulin glulisine qd and tid for the difference in hba1c reduction from baseline. however in this study, adlyxin provided less hba1c reduction than insulin glulisine tid and the difference was statistically significant (p=0.0002). table 11: active-controlled study in patients with type 2 diabetes mellitus in combination with a basal insulin with or without metformin (26-week treatment period results) – itt population adlyxin insulin glulisine qd insulin glulisine tid (n=298) (n=298) (n=298) itt population = all randomized patients. noninferiority margin = 0.4%. 12% of patients in adlyxin, 8% in glulisine qd and 5.0% in glulisine tid had missing hba1c data at week 26 in the itt population. hba1c (%) baseline 7.77 7.73 7.79 ls mean change from baseline using multiple imputation with respect to use the baseline value for missing data at week 26 in each group. -0.57 -0.53 -0.80 ls mean difference vs insulin glulisine -0.04 0.23 95% ci (-0.161 to 0.080) (0.112 to 0.352) (p=0.0002) patients (%) achieving hba1c <7.0% patients with missing hba1c value at week 26 were considered nonresponders. 38.6 36.6 47.7 fasting plasma glucose (fpg) (mg/dl) baseline 118.55 123.21 119.80 ls mean change from baseline -3.39 -3.68 -1.42 body weight (kg) baseline 90.06 88.45 90.08 ls mean change from baseline -0.64 0.98 1.26 ls mean difference vs insulin glulisine -1.91 95% ci (-3.103 to -0.713) (p=0.0018) 14.6 elixa cardiovascular outcome study the elixa study was a randomized, double-blind, placebo-controlled, multinational study that evaluated cardiovascular (cv) outcomes during treatment with adlyxin in patients with type 2 diabetes mellitus after a recent acute coronary syndrome event. the primary composite endpoint was the time to the first occurrence of a major adverse cardiovascular event or mace+, defined as any of the following positively adjudicated events: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, or hospitalization for unstable angina. the study was designed as a noninferiority trial with a prespecified risk margin of 1.3 for the hazard ratio comparing adlyxin to placebo. overall, 6068 patients were randomized 1:1 to either placebo or adlyxin 20 mcg (following a starting dose of 10 mcg during the first 2 weeks) and were included in the primary analyses. the demographics and baseline characteristics were well-balanced between treatments. the median age at study entry was 60 years. approximately 69% of the patients were males and 75% were caucasian. the majority of patients were either obese or overweight with a median bmi of 29.4 kg/m 2 . the mean duration of diabetes was 9.3 years. more than 75% of patients had impaired renal function and more than 20% had an estimated gfr less than 60 ml/min/ 1.73 m 2 . use of cv medications at baseline was similar between treatments; platelet aggregation inhibitors (aspirin and/or clopidogrel) were used by 97.5% of patients, statins by 92.7%, ace inhibitors and/or angiotensin ii antagonists by 86.8%, and beta-blockers by 84.4%. prior to study entry, 93.9% of patients used at least 1 glucose-lowering medication, including metformin (69.9%), sulfonylureas (37.3%) and insulin (47.6%). during the study, antidiabetic medications were adjusted by the investigators per the local standard of care. ninety-six percent of the patients in both treatment groups completed the study in accordance with the protocol, and the vital status was known at the end of the study for 99.0% and 98.6% of the patients in the adlyxin and placebo group, respectively. median treatment duration was 22.4 months in the adlyxin group and 23.3 months in the placebo group, and the median duration of study follow-up was 25.8 and 25.7 months, respectively. the results of the primary composite cardiovascular endpoint are shown in table 12. the hazard ratio (hr) for adlyxin versus placebo was 1.02, with an associated 2-sided 95% confidence interval (ci) of 0.89 to 1.17. the upper bound of this confidence interval, 1.17, excluded a risk margin larger than 1.3. table 12: analysis of the primary cardiovascular endpoint (time to the first occurrence of the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) – itt population placebo (n=3,034) adlyxin (n=3,034) hazard ratio (95% ci) ci: confidence interval, cv: cardiovascular. only positively adjudicated events by the cardiovascular events adjudication committee are included. primary composite cv event 1.02 (0.89, 1.17) no. of patients with event (%) 399 (13.2%) 406 (13.4%) total person year 6328.2 6356.8 incidence rate 6.31 6.39 component cv event cardiovascular death 93 (3.1%) 88 (2.9%) nonfatal myocardial infarction 247 (8.1%) 255 (8.4%) nonfatal stroke 49 (1.6%) 54 (1.8%) hospitalization for unstable angina 10 (0.3%) 9 (0.3%) the kaplan-meier based cumulative event probability is presented in figure 1 for the time to first occurrence of the primary cv composite endpoint by treatment arm. figure 1: kaplan-meier cumulative curves of the primary cv endpoint (time to the first occurrence of the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) – itt population figure 1

cap after each use to protect from light. discard pen 14 days after first use.

person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens [see warnings and precautions (5.3) ] . hypoglycemia with concomitant use of insulin secretagogues or insulin inform patients that the risk of hypoglycemia increased when adlyxin is used in combination with a sulfonylurea or insulin. educate patients on the signs and symptoms of hypoglycemia [see warnings and precautions (5.4) ] . dehydration and renal failure advise patients treated with adlyxin of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. inform patients of the potential risk for worsening renal function, which in some cases may require dialysis [see warnings and precautions (5.5) ] . acute gallbladder disease inform patients of the potential risk for cholelithiasis or cholecystitis. instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up [see warnings and precautions (5.7) ]. use in pregnancy advise patients to inform their physicians if they are pregnant or intend to become pregnant [see use in specific populations (8.1) ] .