Saxenda

WARNING: RISK OF THYROID C-CELL TUMORS • Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether SAXENDA causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions ( 5.1 ) and Nonclinical Toxicology ( 13.1 )] . • SAXENDA is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC with use of SAXENDA and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with SAXENDA [see Contraindications ( 4 ), Warnings and Precautions ( 5.1 )]. WARNING: RISK OF THYROID C-CELL TUMORS See full prescribing information for complete boxed warning. • Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether SAXENDA causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined ( 5.1 ). • SAXENDA is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors ( 4 , 5.1 , 13.1 ).

5 WARNINGS AND PRECAUTIONS • Thyroid C-cell Tumors: See Boxed Warning ( 5.1 ). • Acute Pancreatitis: Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ). • Acute Gallbladder Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated ( 5.3 ). • Hypoglycemia: Can occur in adults when SAXENDA is used with an insulin secretagogue (e.g. a sulfonylurea) or insulin. The risk may be lowered by a reduction in the dose of concomitantly administered insulin secretagogues or insulin. In the pediatric clinical trial, patients did not have type 2 diabetes. Hypoglycemia occurred in SAXENDA-treated pediatric patients. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia ( 2 , 5.4 ). • Heart Rate Increase: Monitor heart rate at regular intervals ( 5.5 ). • Renal Impairment: Has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration which may sometimes require hemodialysis. Use caution when initiating or escalating doses of SAXENDA in patients with renal impairment ( 5.6 ). • Hypersensitivity Reactions: Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue SAXENDA and other suspect medications and promptly seek medical advice ( 5.7 ). • Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue SAXENDA if symptoms develop ( 5.8 ). 5.1 Risk of Thyroid C-cell Tumors Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology ( 13.1 )] . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether SAXENDA will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined. Cases of MTC in patients treated with liraglutide have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and liraglutide use in humans. SAXENDA is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of SAXENDA and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with SAXENDA. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC, and patients with MTC usually have calcitonin values greater than 50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated. 5.2 Acute Pancreatitis Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with liraglutide. After initiation of SAXENDA, 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, SAXENDA should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, SAXENDA should not be restarted. In SAXENDA clinical trials in adults, acute pancreatitis was confirmed by adjudication in 9 (0.3%) of 3291 SAXENDA-treated patients and 2 (0.1%) of 1843 placebo-treated patients. In addition, there were 2 cases of acute pancreatitis in SAXENDA-treated patients who prematurely withdrew from these clinical trials, occurring 74 and 124 days after the last dose. There were 2 additional cases in SAXENDA-treated patients, 1 during an off-treatment follow-up period within 2 weeks of discontinuing SAXENDA, and 1 that occurred in a patient who completed treatment and was off-treatment for 106 days. In a SAXENDA pediatric clinical trial, pancreatitis was not independently adjudicated. Pancreatitis was reported in 1 (0.8%) SAXENDA-treated patient and resulted in treatment discontinuation. Liraglutide has been studied in a limited number of adult patients with a history of pancreatitis. It is unknown if patients with a history of pancreatitis are at higher risk for development of pancreatitis on SAXENDA. 5.3 Acute Gallbladder Disease In SAXENDA clinical trials in adults, 2.2% of SAXENDA-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in SAXENDA-treated patients versus 0.4% in placebo-treated patients. The majority of SAXENDA-treated patients with adverse events of cholelithiasis and cholecystitis required cholecystectomy. Substantial or rapid weight loss can increase the risk of cholelithiasis; however, the incidence of acute gallbladder disease was greater in SAXENDA-treated patients than in placebo-treated patients even after accounting for the degree of weight loss. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated. 5.4 Hypoglycemia Adult patients with type 2 diabetes mellitus on an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia with use of SAXENDA, including severe hypoglycemia. In patients with type 2 diabetes, monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment [see Dosage and Administration ( 2 ) and 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. In the pediatric clinical trial, patients did not have type 2 diabetes but were provided with blood glucose meters. Clinically significant hypoglycemia, defined as blood glucose <54 mg/dL, occurred in 1.6% of the SAXENDA- treated patients compared to 0.8% of placebo-treated patients [see Adverse Reactions ( 6.1 )]. Inform all pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. 5.5 Heart Rate Increase Mean increases in resting heart rate of 2 to 3 beats per minute (bpm) were observed with routine clinical monitoring in SAXENDA-treated adult patients compared to placebo in clinical trials. More patients treated with SAXENDA, compared with placebo, had changes from baseline at two consecutive visits of more than 10 bpm (34% versus 19%, respectively) and 20 bpm (5% versus 2%, respectively). At least one resting heart rate exceeding 100 bpm was recorded for 6% of SAXENDA-treated patients compared with 4% of placebo-treated patients, with this occurring at two consecutive study visits for 0.9% and 0.3%, respectively. Tachycardia was reported as an adverse reaction in 0.6% of SAXENDA-treated patients and in 0.1% of placebo-treated patients. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, SAXENDA treatment was associated with a heart rate that was 4 to 9 bpm higher than that observed with placebo. In a pediatric clinical trial, mean increases from baseline in resting heart rate of 3 to 7 bpm were observed with SAXENDA treatment. Heart rate should be monitored at regular intervals consistent with usual clinical practice. Patients should inform health care providers of palpitations or feelings of a racing heartbeat while at rest during SAXENDA treatment. For patients who experience a sustained increase in resting heart rate while taking SAXENDA, SAXENDA should be discontinued. 5.6 Renal Impairment In patients treated with GLP-1 receptor agonists, including SAXENDA, there have been reports of acute renal failure and worsening of chronic renal failure, sometimes requiring hemodialysis [see Adverse Reactions ( 6.2 )] . 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, or diarrhea leading to volume depletion. Some of the reported events occurred in patients receiving one or more medications known to affect renal function or volume status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including liraglutide. Use caution when initiating or escalating doses of SAXENDA in patients with renal impairment [see Use in Specific Populations ( 8.6 )] . 5.7 Hypersensitivity Reactions There have been reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with SAXENDA [see Contraindications ( 4 ), Adverse Reactions ( 6.1 , 6.2 )] . If a hypersensitivity reaction occurs, the patient should discontinue SAXENDA and other suspect medications and promptly seek medical advice. Anaphylaxis and angioedema have been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of anaphylaxis or angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to these reactions with SAXENDA. 5.8 Suicidal Behavior and Ideation In SAXENDA adult clinical trials, 9 (0.3%) of 3384 SAXENDA-treated patients and 2 (0.1%) of the 1941 placebo-treated patients reported suicidal ideation; one of these SAXENDA-treated patients attempted suicide. In a SAXENDA pediatric clinical trial, 1 (0.8%) of the 125 SAXENDA-treated patients died by suicide. There was insufficient information to establish a causal relationship to SAXENDA. Patients treated with SAXENDA should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue SAXENDA in patients who experience suicidal thoughts or behaviors. Avoid SAXENDA in patients with a history of suicidal attempts or active suicidal ideation.

6 ADVERSE REACTIONS The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-Cell Tumors [see Warnings and Precautions ( 5.1 )] • Acute Pancreatitis [see Warnings and Precautions ( 5.2 )] • Acute Gallbladder Disease [see Warnings and Precautions ( 5.3 )] • Risk for Hypoglycemia with Concomitant Use of Anti-Diabetic Therapy [see Warnings and Precautions ( 5.4 )] • Heart Rate Increase [see Warnings and Precautions ( 5.5 )] • Renal Impairment [see Warnings and Precautions ( 5.6 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.7 )] • Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.8 )] • Most common adverse reactions, reported in greater than or equal to 5% are: nausea, diarrhea, constipation, vomiting, injection site reactions, headache, hypoglycemia, dyspepsia, fatigue, dizziness, abdominal pain, increased lipase, upper abdominal pain, pyrexia, and gastroenteritis ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-844-363-4448 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 studies of another drug and may not reflect the rates observed in practice. SAXENDA was evaluated for safety in 5 double-blind, placebo controlled trials that included 3384 overweight or obese adult patients treated with SAXENDA for a treatment period up to 56 weeks (3 trials), 52 weeks (1 trial), and 32 weeks (1 trial) and one trial of 56 weeks in 125 pediatric patients with obesity aged 12 years and older [see Clinical Studies ( 14.1 , 14.2 )]. All patients received study drug in addition to a reduced-calorie diet and increased physical activity counseling. In the adult trials, patients received SAXENDA for a mean treatment duration of 46 weeks (median, 56 weeks). Baseline characteristics included a mean age of 47 years, 71% women, 85% white, 39% with hypertension, 15% with type 2 diabetes, 34% with dyslipidemia, 29% with a BMI greater than 40 kg/m 2 , and 9% with cardiovascular disease. In one of the 56-week trials, a subset of patients (with abnormal glucose measurements at randomization) [see Clinical Studies ( 14.1 )] were enrolled for a placebo-controlled 160-week period instead, followed by a 12-week off-treatment follow-up. For those participating in this 160-week period, patients received SAXENDA for a mean treatment duration of 110 weeks (median, 159 weeks). For all trials, dosing was initiated and increased weekly to reach the 3 mg dose. In adult clinical trials, 9.8% of patients treated with SAXENDA and 4.3% of patients treated with placebo prematurely discontinued treatment as a result of adverse reactions. The most common adverse reactions leading to discontinuation were nausea (2.9% versus 0.2% for SAXENDA and placebo, respectively), vomiting (1.7% versus less than 0.1%), and diarrhea (1.4% versus 0%). Adverse reactions reported in greater than or equal to 2% of SAXENDA-treated adult patients and more frequently than in placebo-treated patients are shown in Table 4. Adverse reactions reported in greater than or equal to 3% of SAXENDA-treated pediatric patients and more frequently than in placebo-treated patients are shown in Table 5. Table 4. Adverse Reactions Occurring in > 2% of SAXENDA-treated Adult Patients and More Frequently than Placebo Placebo N = 1941 % SAXENDA N = 3384 % Nausea 13.8 39.3 Diarrhea 9.9 20.9 Constipation 8.5 19.4 Vomiting 3.9 15.7 Injection Site Reaction 1 10.5 13.9 Headache 12.6 13.6 Hypoglycemia in T2DM 2 6.6 12.6 Dyspepsia 2.7 9.6 Fatigue 4.6 7.5 Dizziness 5.0 6.9 Abdominal Pain 3.1 5.4 Increased Lipase 2.2 5.3 Upper Abdominal Pain 2.7 5.1 Gastroenteritis 3.2 4.7 Gastroesophageal Reflux Disease 1.7 4.7 Abdominal Distension 3.0 4.5 Eructation 0.2 4.5 Urinary Tract Infection 3.1 4.3 Flatulence 2.5 4.0 Viral Gastroenteritis 1.6 2.8 Insomnia 1.7 2.4 Dry Mouth 1.0 2.3 Asthenia 0.8 2.1 Anxiety 1.6 2.0 1 The most common reactions, each reported by 1% to 2.5% of SAXENDA-treated patients and more commonly than by placebo-treated patients, included erythema, pruritus, and rash at the injection site. 2 Defined as blood glucose <54 mg/dL with or without symptoms of hypoglycemia in patients with type 2 diabetes not on concomitant insulin (Study 2, SAXENDA N=423, Placebo N=212). See text below for further information regarding hypoglycemia in patients with and without type 2 diabetes. T2DM = type 2 diabetes mellitus Table 5 . Adverse Reactions Occurring in > 3% of SAXENDA-treated Pediatric Patients and More Frequently than Placebo in a 56 Week Clinical Trial Placebo N = 126 % SAXENDA N = 125 % Nausea 14.3 42.4 Vomiting 4.0 34.4 Diarrhea 14.3 22.4 Hypoglycemia 1 4.0 15.2 Gastroenteritis 4.8 12.8 Dizziness 3.2 10.4 Pyrexia 7.1 8.0 Abdominal discomfort 0.8 4.8 Constipation 2.4 4.8 Dyslipidemia 3.2 4.8 Fatigue 3.2 4.8 Cough 3.2 4.0 Depression 2.4 4.0 Dyspepsia 2.4 4.0 Pain in extremity 2.4 4.0 Injection site pain 3.2 3.2 Flatulence 0 3.2 Increased Blood Creatine Kinase 2.4 3.2 Increased Lipase 0.8 3.2 Rash 0 3.2 1 Defined as blood glucose <70 mg/dL with symptoms of hypoglycemia. Pediatric patients did not have type 2 diabetes mellitus. See text below for more detailed hypoglycemia information. Hypoglycemia Adult Patients with Type 2 Diabetes In a clinical trial in adult patients with type 2 diabetes mellitus and overweight (excess weight) or obesity, severe hypoglycemia (defined as requiring the assistance of another person) occurred in 3 (0.7%) of 422 SAXENDA-treated patients (all taking a sulfonylurea) and in none of the 212 placebo-treated patients. In this trial, among patients taking a sulfonylurea, hypoglycemia defined as a plasma glucose less than 54 mg/dL with or without symptoms occurred in 31 (28.2%) of 110 SAXENDA-treated patients and 7 (12.7%) of 55 placebo-treated patients. The doses of sulfonylureas were reduced by 50% at the beginning of the trial per protocol. Among patients not taking a sulfonylurea, blood glucose less than 54 mg/dL with or without symptoms occurred in 22 (7.1%) of 312 SAXENDA-treated patients and 7 (4.5%) of 157 placebo-treated patients. In a SAXENDA clinical trial in adult patients with overweight (excess weight) or obesity with type 2 diabetes mellitus treated with basal insulin and SAXENDA in combination with a reduced-calorie diet and increased physical activity and up to 2 oral anti-diabetes medications, severe hypoglycemia was reported by 3 (1.5%) of 195 SAXENDA-treated patients and 2 (1.0%) of 197 placebo-treated patients. No meaningful difference in hypoglycemia, defined as blood glucose less than 54 mg/dL with or without symptoms, was reported between groups. Adult Patients without Type 2 Diabetes In SAXENDA clinical trials in adult patients without type 2 diabetes mellitus, there was no systematic capturing or reporting of hypoglycemia; patients were not provided with blood glucose meters or hypoglycemia diaries. Spontaneously reported symptomatic episodes of unconfirmed hypoglycemia were reported by 46 (1.6%) of 2962 SAXENDA-treated patients and 19 (1.1%) of 1729 placebo-treated patients. Fasting plasma glucose values obtained at routine clinic visits less than 54 mg/dL, irrespective of hypoglycemic symptoms, occurred in 2 (0.1%) SAXENDA-treated patients and 1 (0.1%) placebo-treated patients. Pediatric Patients without Type 2 Diabetes In a 56-week placebo-controlled clinical trial of pediatric patients without type 2 diabetes mellitus in which blood glucose meters were provided, 19 (15.2%) of SAXENDA-treated patients had hypoglycemia with a blood glucose less than 70 mg/dL with symptoms as compared to 5 (4.0%) of placebo-treated patients. Four (4) events of hypoglycemia defined as a plasma glucose less than 54 mg/dL occurred in 2 (1.6%) of 125 SAXENDA-treated patients and 1 event occurred in 1 (0.8%) of 126 placebo-treated patients. No severe hypoglycemic episodes, defined as requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions, occurred in the SAXENDA treatment group. Gastrointestinal Adverse Reactions In the adult clinical trials, approximately 68% of SAXENDA-treated patients and 39% of placebo-treated patients reported gastrointestinal disorders; the most frequently reported was nausea (39% and 14% of patients treated with SAXENDA and placebo, respectively). The percentage of patients reporting nausea declined as treatment continued. Other common adverse reactions that occurred at a higher incidence among SAXENDA-treated patients included diarrhea, constipation, vomiting, dyspepsia, abdominal pain, dry mouth, gastritis, gastroesophageal reflux disease, flatulence, eructation and abdominal distension. Most episodes of gastrointestinal events were mild or moderate and did not lead to discontinuation of therapy (6.2% with SAXENDA versus 0.8% with placebo discontinued treatment as a result of gastrointestinal adverse reactions). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment. In a pediatric clinical trial, 8.0% of patients treated with SAXENDA versus no patients who received placebo discontinued treatment as a result of gastrointestinal adverse reactions. Most adverse reactions leading to discontinuation were due to vomiting and nausea (4.8% and 3.2% of SAXENDA-treated patients, respectively). Asthenia, Fatigue, Malaise, Dysgeusia and Dizziness Events of asthenia, fatigue, malaise, dysgeusia and dizziness were mainly reported within the first 12 weeks of treatment with SAXENDA and were often co-reported with gastrointestinal events such as nausea, vomiting, and diarrhea. Immunogenicity 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 SAXENDA cannot be directly compared with the incidence of antibodies of other products. Patients treated with SAXENDA may develop anti-liraglutide antibodies. Anti-liraglutide antibodies were detected in 42 (2.8%) of 1505 SAXENDA-treated adult patients with a post-baseline assessment. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 18 (1.2%) of 1505 SAXENDA-treated patients. Presence of antibodies may be associated with a higher incidence of injection site reactions and reports of low blood glucose. In clinical trials, these events were usually classified as mild and resolved while patients continued on treatment. In a pediatric clinical trial, anti-liraglutide antibodies were detected in 14 (12%) of 117 SAXENDA-treated patients with a post-baseline assessment; 5 (4.3%) had persistent antibodies as defined by more than 2 antibody visits at least 16 weeks apart. Two patients (1.7%) remained positive throughout the follow-up period; 1 (0.9%) had antibodies cross reactive to native GLP-1. No patients had neutralizing antibodies. Allergic Reactions Urticaria was reported in 0.7% of SAXENDA-treated patients and 0.5% of placebo-treated patients. Anaphylactic reactions, asthma, bronchial hyperreactivity, bronchospasm, oropharyngeal swelling, facial swelling, angioedema, pharyngeal edema, type IV hypersensitivity reactions have been reported in patients treated with liraglutide in clinical trials. Cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnea, and edema have been reported with marketed use of liraglutide. Anaphylactic reactions may potentially be life-threatening. Breast Cancer In SAXENDA clinical trials in adults, breast cancer confirmed by adjudication was reported in 17 (0.7%) of 2379 SAXENDA-treated women compared with 3 (0.2%) of 1300 placebo-treated women, including invasive cancer (13 SAXENDA- and 2 placebo-treated women) and ductal carcinoma in situ (4 SAXENDA- and 1 placebo-treated woman). The majority of cancers were estrogen- and progesterone-receptor positive. There were too few cases to determine whether these cases were related to SAXENDA. In addition, there are insufficient data to determine whether SAXENDA has an effect on pre-existing breast neoplasia. Papillary Thyroid Cancer In SAXENDA clinical trials in adults, papillary thyroid carcinoma confirmed by adjudication was reported in 8 (0.2%) of 3291 SAXENDA-treated patients compared with no cases among 1843 placebo-treated patients. Four of these papillary thyroid carcinomas were less than 1 cm in greatest diameter and 4 were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings identified prior to treatment. Colorectal Neoplasms In SAXENDA clinical trials in adults, benign colorectal neoplasms (mostly colon adenomas) confirmed by adjudication were reported in 20 (0.6%) of 3291 SAXENDA-treated patients compared with 7 (0.4%) of 1843 placebo-treated patients. Six positively adjudicated cases of malignant colorectal neoplasms were reported in 5 SAXENDA-treated patients (0.2%, mostly adenocarcinomas) and 1 in a placebo-treated patient (0.1%, neuroendocrine tumor of the rectum). Cardiac Conduction Disorders In SAXENDA clinical trials in adults, 11 (0.3%) of 3384 SAXENDA-treated patients compared with none of the 1941 placebo-treated patients had a cardiac conduction disorder, reported as first degree atrioventricular block, right bundle branch block, or left bundle branch block. Hypotension Adverse reactions related to hypotension (hypotension, orthostatic hypotension, circulatory collapse, and decreased blood pressure) were reported more frequently with SAXENDA (1.1%) compared with placebo (0.5%) in SAXENDA clinical trials in adults. Systolic blood pressure decreases to less than 80 mmHg were observed in 4 (0.1%) SAXENDA-treated patients compared with no placebo-treated patients. One of the SAXENDA-treated patients had hypotension associated with gastrointestinal adverse reactions and renal failure [see Warnings and Precautions ( 5.6 )] . Laboratory Abnormalities Liver Enzymes Increases in alanine aminotransferase (ALT) greater than or equal to 10 times the upper limit of normal were observed in 5 (0.15%) SAXENDA-treated patients (two of whom had ALT greater than 20 and 40 times the upper limit of normal) compared with 1 (0.05%) placebo-treated patient during the SAXENDA clinical trials. Because clinical evaluation to exclude alternative causes of ALT and aspartate aminotransferase (AST) increases was not done in most cases, the relationship to SAXENDA is uncertain. Some increases in ALT and AST were associated with other confounding factors (such as gallstones). Serum Calcitonin Calcitonin, a biological marker of MTC, was measured throughout the clinical development program [see Warnings and Precautions ( 5.1 )] . More patients treated with SAXENDA in the clinical trials were observed to have high calcitonin values during treatment, compared with placebo. The proportion of patients with calcitonin greater than or equal to 2 times the upper limit of normal at the end of the trial was 1.2% in SAXENDA-treated patients and 0.6% in placebo-treated patients. Calcitonin values greater than 20 ng/L at the end of the trial occurred in 0.5% of SAXENDA-treated patients and 0.2% of placebo-treated patients; among patients with pre-treatment serum calcitonin less than 20 ng/L, none had calcitonin elevations to greater than 50 ng/L at the end of the trial. Serum Lipase and Amylase Serum lipase and amylase were routinely measured in the SAXENDA clinical trials. Among SAXENDA-treated patients, 2.1% had a lipase value at anytime during treatment of greater than or equal to 3 times the upper limit of normal compared with 1.0% of placebo-treated patients. 0.1% of SAXENDA-treated patients had an amylase value at anytime in the trial of greater than or equal to 3 times the upper limit of normal versus 0.1% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with SAXENDA is unknown in the absence of other signs and symptoms of pancreatitis [see Warnings and Precautions ( 5.2 )] . 6.2 Post Marketing Experience The following adverse reactions have been reported during post-approval use of liraglutide, the active ingredient of SAXENDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Neoplasms Medullary thyroid carcinoma Gastrointestinal Disorders Acute pancreatitis, hemorrhagic and necrotizing pancreatitis, sometimes resulting in death, ileus Metabolism and Nutrition Disorders Dehydration resulting from nausea, vomiting and diarrhea Renal and Urinary Disorders Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis General Disorders and Administration Site Conditions Allergic reactions: rash and pruritus Immune System Disorders Angioedema and anaphylactic reactions Hepatobiliary Disorders Hyperbilirubinemia, elevations of liver enzymes, cholestasis and hepatitis Skin and Subcutaneous Tissue Disorders Cutaneous amyloidosis

<table width="457.35pt"><col width="58%"/><col width="20%"/><col width="18%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N = 1941</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">SAXENDA</content></paragraph><paragraph><content styleCode="bold">N = 3384</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Nausea</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>39.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Diarrhea</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20.9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Constipation</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8.5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Vomiting</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Injection Site Reaction¹</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10.5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13.9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Headache</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>13.6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Hypoglycemia in T2DM²</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12.6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Dyspepsia</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9.6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Fatigue</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Dizziness</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6.9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Abdominal Pain</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Increased Lipase </item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Upper Abdominal Pain</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5.1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Gastroenteritis</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Gastroesophageal Reflux Disease</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Abdominal Distension</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Eructation</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Urinary Tract Infection</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Flatulence</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Viral Gastroenteritis </item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Insomnia</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.7</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Dry Mouth</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Asthenia</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.1</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><list listType="ordered"><item><caption> </caption>Anxiety</item></list></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.6</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2.0</paragraph></td></tr></tbody></table>

<table width="82.52%"><col width="58%"/><col width="21%"/><col width="17%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">N = 126</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">SAXENDA</content></paragraph><paragraph><content styleCode="bold">N = 125</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Nausea</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>42.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Vomiting</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>34.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Diarrhea</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14.3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>22.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Hypoglycemia¹</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Gastroenteritis</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Dizziness</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10.4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Pyrexia</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7.1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Abdominal discomfort</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Constipation</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Dyslipidemia</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Fatigue</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Cough</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Depression</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Dyspepsia</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Pain in extremity</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Injection site pain</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Flatulence</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Increased Blood Creatine Kinase</item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><list listType="ordered"><item><caption> </caption>Increased Lipase </item></list></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.8</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3.2</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><list listType="ordered"><item><caption> </caption>Rash</item></list></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3.2</paragraph></td></tr></tbody></table>