LIRAGLUTIDE: 23,119 Adverse Event Reports & Safety Profile

Liraglutide Injection contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae , has been engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor. The molecular formula of liraglutide is C 172 H 265 N 43 O 51 and the molecular weight is 3,751.2 Daltons. The structural formula ( Figure 1 ) is: Figure 1.

Structural

Formula of Liraglutide Liraglutide Injection is a sterile, aqueous, clear, colorless or almost colorless solution for subcutaneous use.

Each

1 mL of Liraglutide Injection solution contains 6 mg of liraglutide and the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14 mg; phenol, 5.5 mg; and water for injection.

Liraglutide

Injection has a pH of approximately 8.15, hydrochloric acid or sodium hydroxide may be added to adjust pH. Each prefilled pen contains a 3 mL solution of Liraglutide Injection equivalent to 18 mg liraglutide (free-base, anhydrous).

Structural

Formula

AND USAGE SAXENDA is indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in:

• Adult patients with an initial body mass index (BMI) of [see Dosage and Administration ( 2.1 )] :
• 30 kg/m 2 or greater (obese), or
• 27 kg/m 2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)
• Pediatric patients aged 12 years and older with:
• body weight above 60 kg and
• an initial BMI corresponding to 30 kg/m 2 or greater for adults (obese) by international cut-offs (Cole Criteria, Table 2) [see Dosage and Administration ( 2.1 )] Limitations of Use
• SAXENDA contains liraglutide and should not be coadministered with other liraglutide-containing products or with any other GLP-1 receptor agonist.
• The safety and effectiveness of SAXENDA in pediatric patients with type 2 diabetes have not been established.
• The safety and effectiveness of SAXENDA in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established. SAXENDA is a glucagon like peptide 1 (GLP-1) receptor agonist indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in: Adult patients with an initial body mass index (BMI) of
• 30 kg/m 2 or greater (obese), or
• 27 kg/m 2 or greater (overweight) in the presence of at least one weight-related comorbid condition (e.g. hypertension, type 2 diabetes mellitus, or dyslipidemia) ( 1 ). Pediatric patients aged 12 years and older with:
• body weight above 60 kg and
• an initial BMI corresponding to 30 kg/m 2 for adults (obese) by international cut-offs ( 1 ). Limitations of Use:
• SAXENDA contains liraglutide and should not be coadministered with other liraglutide-containing products or with any other GLP-1 receptor agonist ( 1 ).
• The safety and effectiveness of SAXENDA in pediatric patients with type 2 diabetes have not been established ( 1 ).
• The safety and efficacy of SAXENDA in combination with other products intended for weight loss have not been established ( 1) .

AND ADMINISTRATION

• Inject SAXENDA subcutaneously in the abdomen, thigh, or upper arm once daily at any time of day, without regard to the timing of meals ( 2.2 ).
• The recommended dose of SAXENDA is 3 mg daily ( 2.3 ).
• Initiate at 0.6 mg per day for one week. In weekly intervals, increase the dose until a dose of 3 mg is reached ( 2.3 ).
• If pediatric patients do not tolerate an increased dose during dose escalation, the dose may also be lowered to the previous level. Dose escalation for pediatric patients may take up to 8 weeks ( 2.3 ).
• Pediatric patients who do not tolerate 3 mg daily may have their dose reduced to 2.4 mg daily ( 2.3 ).
• Adult patients with type 2 diabetes should monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment ( 2.3 ).

2.1 Patient Selection Select patients for SAXENDA treatment as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management based on the BMI values provided in Tables 1 and 2. Adult and Pediatric Patients BMI is calculated by dividing weight in (kilograms) by height (in meters) squared. A chart for determining BMI based on height and weight is provided in Table 1.

Table

1: BMI Conversion Chart Pediatric Patients Aged 12 Years and Older BMI cut-offs for obesity in pediatric patients aged 12 years and older are presented in Table 2.

Table

2: International Obesity Task Force BMI Cut-offs for Obesity by Sex and Age for Pediatric Patients Aged 12 Years and Older (Cole Criteria) Age (years) Body mass index 30 kg/m 2 Males Females 12 26.02 26.67 12.5 26.43 27.24 13 26.84 27.76 13.5 27.25 28.20 14 27.63 28.57 14.5 27.98 28.87 15 28.30 29.11 15.5 28.60 29.29 16 28.88 29.43 16.5 29.14 29.56 17 29.41 29.69 17.5 29.70

29.84 Table

2.2 Important Administration Instructions

• Prior to initiation of SAXENDA, train patients on proper injection technique. Refer to the accompanying Instructions for Use for complete administration instructions with illustrations.
• Inspect SAXENDA visually prior to each injection. Only use if solution is clear, colorless, and contains no particles.
• Inject SAXENDA subcutaneously once daily at any time of day, without regard to the timing of meals.
• Inject SAXENDA subcutaneously in the abdomen, thigh, or upper arm. No dose adjustment is needed if changing the injection site and/or timing.
• Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis [see Adverse Reactions ( 6.2 )].
• If a dose is missed, resume the once-daily regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose.
• If more than 3 days have elapsed since the last SAXENDA dose, reinitiate SAXENDA at 0.6 mg daily and follow the dose escalation schedule in Table 3, to reduce the occurrence of gastrointestinal adverse reactions associated with reinitiation of treatment.

2.3 Dosage in Adults and Pediatric Patients Aged 12 Years and Older

• Initiate SAXENDA with a dose of 0.6 mg daily for one week. Then follow the dose escalation schedule in Table 3 to minimize gastrointestinal adverse reactions [see Adverse Reactions ( 6.1 )] .

Table

3: Dose Escalation Schedule Week Daily Dose 1 0.6 mg 2 1.2 mg 3 1.8 mg 4 2.4 mg 5 and onward 3 mg Adult Patients

• For adults, the recommended dosage of SAXENDA is 3 mg daily, lower doses are for titration only.
• Discontinue SAXENDA if the patient cannot tolerate the 3 mg dose.
• If patients do not tolerate an increased dose during dose escalation, consider delaying dose escalation for approximately one additional week.
• Evaluate the change in body weight 16 weeks after initiating SAXENDA and discontinue SAXENDA if the patient has not lost at least 4% of baseline body weight, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
• In adult patients with type 2 diabetes, monitor blood glucose prior to starting SAXENDA and during SAXENDA treatment.

Pediatric

Patients

• For pediatric patients, the recommended maintenance dosage of SAXENDA is 3 mg daily. Pediatric patients who do not tolerate 3 mg daily may have their maintenance dose reduced to 2.4 mg daily. Discontinue SAXENDA if the patient cannot tolerate the 2.4 mg dose.
• If pediatric patients do not tolerate an increased dose during dose escalation, the dose may also be lowered to the previous level. Dose escalation for pediatric patients may take up to 8 weeks.
• Evaluate the change in BMI after 12 weeks on the maintenance dose and discontinue SAXENDA if the patient has not had a reduction in BMI of at least 1% from baseline, since it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

4 CONTRAINDICATIONS

• Medullary Thyroid Carcinoma VICTOZA is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
• Hypersensitivity VICTOZA is contraindicated in patients with a serious hypersensitivity reaction to liraglutide or to any of the excipients in VICTOZA. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with VICTOZA [see Warnings and Precautions ( 5.6 )]. VICTOZA is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4) . VICTOZA is contraindicated in patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in VICTOZA (4) .

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 )]
• Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ( 5.6 )]
• Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ( 5.7 )]
• Hypersensitivity Reactions [see Warnings and Precautions ( 5.8 )]
• Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.9 )]
• Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ( 5.10 )] 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 , 14.2 )]</span>. 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% female, 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) <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span> 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 2 . 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 3 .

Table

2.

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

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

4.5 Eructation 0.2

4.5 Urinary Tract Infection 3.1

4.3 Flatulence 2.5 4 Viral Gastroenteritis 1.6

2.8 Insomnia 1.7

2.4 Dry Mouth 1

2.3 Asthenia 0.8

2.1 Anxiety 1.6 2 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 &lt;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

3.

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

34.4 Diarrhea 14.3

22.4 Hypoglycemia 1 4

15.2 Gastroenteritis 4.8

12.8 Dizziness 3.2

10.4 Pyrexia 7.1 8 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 Depression 2.4 4 Dyspepsia 2.4 4 Pain in extremity 2.4 4 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 &lt;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%) 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%) 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.

Acute

Pancreatitis 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.

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). Severe gastrointestinal adverse reactions were reported more frequently among patients receiving SAXENDA (4.8%) than placebo (1.4 %). There have been reports of gastrointestinal adverse reactions, such as nausea, vomiting, and diarrhea, associated with volume depletion and renal impairment. 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). 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. 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% 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).

Cardiovascular Safety

Cardiovascular safety was assessed (LEADER, NCT01179048) in 9,340 patients with inadequately controlled type 2 diabetes and cardiovascular disease randomized to liraglutide 1.8 mg or placebo in addition to standard of care treatments for type 2 diabetes for a median duration of 3.5 years. The primary endpoint was the time from randomization to first occurrence of a major adverse cardiovascular event (MACE) defined as: cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. No increased risk for MACE was observed with liraglutide 1.8 mg. The total number of primary component MACE endpoints was 1,302 [608 (13.0%) with liraglutide 1.8 mg and 694 (14.9%) with placebo].

Liraglutide

1.8 mg (Victoza) is used in the treatment of type 2 diabetes mellitus in adults. The efficacy of liraglutide at doses below 3 mg daily has not been established for weight reduction. 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 Postmarketing 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.

Gastrointestinal

Acute pancreatitis; hemorrhagic and necrotizing pancreatitis, sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction, nausea, vomiting and diarrhea leading to dehydration Hepatobiliary Hyperbilirubinemia, elevations of liver enzymes, cholestasis and hepatitis Hypersensitivity Rash, pruritus, angioedema and anaphylactic reactions Neoplasms Medullary thyroid carcinoma Neurologic Dysesthesia, headache Pulmonary Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.

Renal

Acute kidney injury, sometimes requiring hemodialysis; increased serum creatinine General Disorders and Administration Site Conditions Allergic reactions: rash and pruritus Immune System Angioedema and anaphylactic reactions Skin and Subcutaneous Tissue Cutaneous amyloidosis, alopecia

AND PRECAUTIONS Acute Pancreatitis: Has been observed in patients treated with GLP-1 receptor agonists, including liraglutide. Discontinue if pancreatitis is suspected. ( 5.2 )

Acute Gallbladder

Disease: If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. ( 5.3 ) Hypoglycemia: Can occur in adults when liraglutide 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 liraglutide-treated pediatric patients. Inform all patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. ( 5.4 )

Heart Rate

Increase: Monitor heart rate at regular intervals. ( 5.5 )

Acute Kidney Injury

Due to Volume Depletion: Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. ( 5.6 )

Severe Gastrointestinal Adverse

Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. Liraglutide is not recommended in patients with severe gastroparesis. ( 5.7 )

Hypersensitivity

Reactions: Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue liraglutide and other suspect medications and promptly seek medical advice. ( 5.8 )

Suicidal

Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue liraglutide if symptoms develop. ( 5.9 )

Pulmonary Aspiration During General

Anesthesia or Deep Sedation: Has been reported in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures. Instruct patients to inform healthcare providers of any planned surgeries or procedures. ( 5.10 )

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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.1 )]</span> . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether liraglutide 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. Liraglutide 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 liraglutide 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 liraglutide. 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 Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists, including liraglutide <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . After initiation of liraglutide, 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, discontinue liraglutide injection and initiate appropriate management.

5.3 Acute Gallbladder Disease In liraglutide clinical trials in adults, 2.2% of liraglutide-treated patients reported adverse events of cholelithiasis versus 0.8% of placebo-treated patients. The incidence of cholecystitis was 0.8% in liraglutide-treated patients versus 0.4% in placebo-treated patients. The majority of liraglutide-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 liraglutide-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 liraglutide, including severe hypoglycemia. In patients with type 2 diabetes, monitor blood glucose prior to starting liraglutide and during liraglutide treatment <span class="opacity-50 text-xs">[see Dosage and Administration ( 2 ) and Adverse Reactions ( 6.1 )]</span> . 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 &lt;54 mg/dL, occurred in 1.6% of the liraglutide-treated patients compared to 0.8% of placebo-treated patients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span>. 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 liraglutide-treated adult patients compared to placebo in clinical trials. More patients treated with liraglutide, 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 liraglutide-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 liraglutide-treated patients and in 0.1% of placebo-treated patients. In a clinical pharmacology trial that monitored heart rate continuously for 24 hours, liraglutide 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 liraglutide 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 liraglutide treatment. For patients who experience a sustained increase in resting heart rate while taking liraglutide, liraglutide should be discontinued.

5.6 Acute Kidney Injury Due to Volume Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with liraglutide <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . The majority of the reported events occurred in patients who had experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Monitor renal function in patients reporting adverse reactions to liraglutide that could lead to volume depletion, especially during dosage initiation and escalation <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 )]</span> .

5.7 Severe Gastrointestinal Adverse Reactions Use of GLP-1 receptor agonists, including liraglutide, has been associated with gastrointestinal adverse reactions, sometimes severe <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> . In liraglutide clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving liraglutide (4.8%) than placebo (1.4 %). Liraglutide is not recommended in patients with severe gastroparesis.

5.8 Hypersensitivity Reactions There have been reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with liraglutide <span class="opacity-50 text-xs">[see Contraindications ( 4 ) and Adverse Reactions ( 6.1 , 6.2 )]</span> . If a hypersensitivity reaction occurs, the patient should discontinue liraglutide injection 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 liraglutide.

5.9 Suicidal Behavior and Ideation In liraglutide adult clinical trials, 9 (0.3%) of 3,384 liraglutide-treated patients and 2 (0.1%) of the 1,941 placebo-treated patients reported suicidal ideation; one of these liraglutide-treated patients attempted suicide. In a liraglutide pediatric clinical trial, 1 (0.8%) of the 125 liraglutide-treated patients died by suicide. There was insufficient information to establish a causal relationship to liraglutide. Patients treated with liraglutide should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Discontinue liraglutide in patients who experience suicidal thoughts or behaviors. Avoid liraglutide in patients with a history of suicidal attempts or active suicidal ideation.

5.10 Pulmonary Aspiration During General Anesthesia or Deep Sedation Liraglutide delays gastric emptying <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.2 )]</span> . There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking liraglutide, including whether modifying preoperative fasting recommendations or temporarily discontinuing liraglutide could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking liraglutide.

INTERACTIONS Effects of delayed gastric emptying on oral medications: Liraglutide injection delays gastric emptying and may impact absorption of concomitantly administered oral medications ( 7 ).

7.1 Effects of Delayed Gastric Emptying on Oral Medications Liraglutide injection causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, liraglutide injection did not affect the absorption of the tested orally administered medications to any clinically relevant degree <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Nonetheless, caution should be exercised when oral medications are concomitantly administered with liraglutide injection.

7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin Liraglutide injection stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving liraglutide injection in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating liraglutide injection, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )]</span>.