Victoza

1 INDICATIONS AND USAGE VICTOZA is indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus, • to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease. Limitations of Use: VICTOZA contains liraglutide. Coadministration with other liraglutide-containing products is not recommended.

VICTOZA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated: • as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus. • to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease. Limitations of Use : • Coadministration with other liraglutide-containing products is not recommended.

2 DOSAGE AND ADMINISTRATION • Adult Patients : Initiate at 0.6 mg injected subcutaneously once daily for one week then increase to 1.2 mg daily. If additional glycemic control is required, increase the dose to 1.8 mg daily after one week of treatment with the 1.2 mg daily dose. • Pediatric Patients : Initiate at 0.6 mg injected subcutaneously once daily for at least one week. If additional glycemic control is required increase the dose to 1.2 mg daily and if additional glycemic control is still required, increase the dose to 1.8 mg daily after at least one week of treatment with the 1.2 mg daily dose. • Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. • Inject VICTOZA subcutaneously once-daily at any time of day, independently of meals, in the abdomen, thigh or upper arm. • When using VICTOZA with insulin, administer as separate injections. Never mix.

2.1Recommended Dosage Adult Patients

• The recommended starting dosage of VICTOZA is 0.6 mg injected subcutaneously once daily for one week. The 0.6 mg once daily dosage is intended to reduce the risk of gastrointestinal adverse reactions during initial titration and is not effective for glycemic control in adults. • After one week at the 0.6 mg once daily dosage, increase the dosage to 1.2 mg injected subcutaneously once daily. • If additional glycemic control is required, increase the dosage to the maximum recommended dosage of 1.8 mg injected subcutaneously once daily after at least one week of treatment with the 1.2 mg once daily dosage. Pediatric Patients Aged 10 Years and Older • The recommended starting dosage of VICTOZA is 0.6 mg injected subcutaneously once daily. • If additional glycemic control is required, increase the dosage in 0.6 mg increments after at least one week on the current dosage, to reduce the risk of gastrointestinal adverse reactions . • The maximum recommended dosage is 1.8 mg injected subcutaneously once daily.

2.2Recommendations Regarding Missed Dose

• Instruct patients who miss a dose of VICTOZA to resume the once daily dosage 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 VICTOZA dose, reinitiate VICTOZA at 0.6 mg once daily to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment. Upon reinitiation, VICTOZA should be titrated at the discretion of the healthcare provider.

2.3Important Administration Instructions

• Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles. • Inject VICTOZA subcutaneously once daily at any time of day, independently of meals. • Inject VICTOZA subcutaneously in the abdomen, thigh or upper arm. No dosage 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 . • When using VICTOZA with insulin, administer as separate injections.

Never mix. It is acceptable to inject VICTOZA and insulin in the same body region but the injections should not be adjacent to each other.

5 WARNINGS AND PRECAUTIONS • Acute Pancreatitis : Has been observed in patients treated with GLP-1 receptor agonists, including VICTOZA. Discontinue if pancreatitis is suspected. • Never Share a VICTOZA Pen Between Patients , even if the needle is changed. • Hypoglycemia : Adult patients taking an insulin secretagogue or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with VICTOZA regardless of insulin and/or metformin use. Reduction in the dose of insulin secretagogues or insulin may be necessary. • Acute Kidney Injury Due to Volume Depletion : Monitor renal function in patients reporting adverse reactions that could lead to volume depletion. • Severe Gastrointestinal Adverse Reactions: Use has been associated with gastrointestinal adverse reactions, sometimes severe. VICTOZA is not recommended in patients with severe gastroparesis. • Hypersensitivity Reactions : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue VICTOZA and promptly seek medical advice. • Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated. • 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.

5.1Risk 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 . Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether VICTOZA 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 VICTOZA have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and VICTOZA use in humans.

VICTOZA 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 VICTOZA 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 VICTOZA. 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 >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.

5.2Acute 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 . After initiation of VICTOZA, observe patients carefully for signs and symptoms of acute pancreatitis which may include persistent or severe abdominal pain (sometimes radiating to the back) and which may or may not be accompanied by nausea or vomiting. If pancreatitis is suspected, discontinue VICTOZA and initiate appropriate management.

5.3Never Share a

VICTOZA Pen Between Patients VICTOZA pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.

5.4Hypoglycemia Adult

patients receiving VICTOZA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. In pediatric patients 10 years of age and older, the risk of hypoglycemia was higher with VICTOZA regardless of insulin and/or metformin use. . 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 and pediatric patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia.

5.5Acute Kidney Injury Due to Volume

Depletion There have been postmarketing reports of acute kidney injury, in some cases requiring hemodialysis, in patients treated with VICTOZA . The majority of the reported events occurred in patients who experienced gastrointestinal reactions leading to dehydration such as nausea, vomiting, or diarrhea . Monitor renal function in patients reporting adverse reactions to VICTOZA that could lead to volume depletion, especially during dosage initiation and escalation of VICTOZA. .

5.6Severe Gastrointestinal Adverse Reactions Use

of GLP-1 receptor agonists, including liraglutide, has been associated with gastrointestinal adverse reactions, sometimes severe . In VICTOZA clinical trials, severe gastrointestinal adverse reactions were reported more frequently among patients receiving VICTOZA (1.2 mg 4.4%, 1.8 mg 4.2%) than placebo (1.1%). Severe gastrointestinal adverse reactions have also been reported postmarketing with GLP-1 receptor agonists. VICTOZA is not recommended in patients with severe gastroparesis.

5.7Hypersensitivity Reactions There

have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with VICTOZA . If a hypersensitivity reaction occurs, discontinue VICTOZA; treat promptly per standard of care, and monitor until signs and symptoms resolve. 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-receptor agonist because it is unknown whether such patients will be predisposed to these reactions with VICTOZA. VICTOZA is contraindicated in patients who have had a serious hypersensitivity reaction to liraglutide or any of the excipients in VICTOZA .

5.8Acute 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 LEADER trial , 3.1% of VICTOZA-treated patients versus 1.9% of placebo-treated patients reported an acute event of gallbladder disease, such as cholelithiasis or cholecystitis . If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

5.9Pulmonary Aspiration During General Anesthesia

or Deep Sedation VICTOZA delays gastric emptying . 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 VICTOZA, including whether modifying preoperative fasting recommendations or temporarily discontinuing VICTOZA 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 VICTOZA.

4 CONTRAINDICATIONS 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) . • 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 . • Patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2. • Patients with a serious hypersensitivity reaction to liraglutide or any of the excipients in VICTOZA.

8.1Pregnancy Risk Summary Based on

animal reproduction studies, there may be risks to the fetus from exposure to VICTOZA during pregnancy. VICTOZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy.

Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD . The estimated background risk of major birth defects for women with uncontrolled pre-gestational diabetes (Hemoglobin A 1c >7) is 6 to 10%. The major birth defect rate has been reported to be as high as 20 to 25% in women with a Hemoglobin A 1c >10. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 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, still birth, and macrosomia related morbidity. Animal Data Female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison.

The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose.

The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels).

Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group.

In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times human exposure at the MRHD of 1.8 mg/day, based on plasma AUC. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day liraglutide.

Group mean body weight from birth to postpartum day 14 trended lower in F 2 generation rats descended from liraglutide-treated rats compared to F 2 generation rats descended from controls, but differences did not reach statistical significance for any group.

8.2Lactation Risk Summary There

are no data on the presence of VICTOZA in human milk, the effects on the breastfed infant, or the effects on milk production. Liraglutide was present in milk of lactating rats . Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VICTOZA and any potential adverse effects on the breastfed infant from VICTOZA or from the underlying maternal condition. Data In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations.

The following serious adverse reactions are described below or elsewhere in the prescribing information: • Risk of Thyroid C-cell Tumors • Acute Pancreatitis • Hypoglycemia • Acute Kidney Injury Due to Volume Depletion • Severe Gastrointestinal Adverse Reactions • Hypersensitivity Reactions • Acute Gallbladder Disease • Pulmonary Aspiration During General Anesthesia or Deep Sedation • Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation. • Immunogenicity-related events, including urticaria, were more common among VICTOZA-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience Because

clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of VICTOZA in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older . The data in Table 1 reflect exposure of 1,673 adult patients to VICTOZA and a mean duration of exposure to VICTOZA of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male.

The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of VICTOZA for the treatment of type 2 diabetes mellitus.

These adverse reactions occurred more commonly on VICTOZA than on placebo and occurred in at least 5% of patients treated with VICTOZA. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1. Adverse reactions reported in ≥5% of Adult Patients Treated with VICTOZA for Type 2 Diabetes Mellitus Placebo N=661 Liraglutide 1.2 mg N= 645 Liraglutide 1.8 mg N= 1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights.

In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of VICTOZA-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving VICTOZA (1.2 mg 4.4%, 1.8 mg 4.2%) than placebo (1.1%). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials.

Injection site reactions Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of VICTOZA-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of VICTOZA-treated patients discontinued due to injection site reactions. Hypoglycemia In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 VICTOZA-treated patients (7.5 events per 1,000 patient-years).

Of these 8 VICTOZA-treated patients, 7 patients were concomitantly using a sulfonylurea. Table 2. Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-Week Combination Therapy Placebo-controlled Trials Placebo Comparator VICTOZA Treatment Add-on to Metformin Placebo + Metformin (N=121) VICTOZA + Metformin (N=724) Patient not able to self-treat 0

0.1Patient

able to self-treat 2.5

3.6Add-on to Glimepiride Placebo

+ Glimepiride (N=114) VICTOZA + Glimepiride (N=695) Patient not able to self-treat 0

0.1Patient

able to self-treat 2.6

7.5Not

classified 0

0.9Add-on to Metformin

+ Rosiglitazone Placebo + Metformin + Rosiglitazone (N=175) VICTOZA + Metformin + Rosiglitazone (N=355) Patient not able to self-treat 0 0 Patient able to self-treat 4.6

7.9Not

classified 1.1

0.6Add-on to Metformin

+ Glimepiride Placebo + Metformin + Glimepiride (N=114) VICTOZA + Metformin + Glimepiride (N=230) Patient not able to self-treat 0

2.2Patient

able to self-treat 16.7

27.4Not

classified 0 0 “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment. In a 26-week placebo-controlled clinical trial in pediatric patients 10 years of age and older with a 26-week open-label extension, 21.2% of VICTOZA-treated patients (mean age 14.6 years) with type 2 diabetes mellitus, had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms (335 events per 1,000 patient years). No severe hypoglycemic episodes occurred in the VICTOZA treatment group (severe hypoglycemia was defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions).

Papillary thyroid carcinoma In adult glycemic control trials of VICTOZA, there were 7 reported cases of papillary thyroid carcinoma in patients treated with VICTOZA and 1 case in a comparator-treated patient (1.5 vs. 0.5 cases per 1,000 patient-years). Most of these papillary thyroid carcinomas were <1 cm in greatest diameter and were diagnosed in surgical pathology specimens after thyroidectomy prompted by findings on protocol-specified screening with serum calcitonin or thyroid ultrasound. Pancreatitis In glycemic control trials of VICTOZA, there have been 13 cases of pancreatitis among VICTOZA-treated patients and 1 case in a comparator (glimepiride) treated patient (2.7 vs. 0.5 cases per 1,000 patient-years).

Nine of the 13 cases with VICTOZA were reported as acute pancreatitis and four were reported as chronic pancreatitis. In one case in a VICTOZA-treated patient, pancreatitis, with necrosis, was observed and led to death; however clinical causality could not be established. Some patients had other risk factors for pancreatitis, such as a history of cholelithiasis or alcohol abuse.

Cholelithiasis and cholecystitis In adult glycemic control trials of VICTOZA, the incidence of cholelithiasis was 0.3% in both VICTOZA-treated and placebo-treated patients. The incidence of cholecystitis was 0.2% in both VICTOZA-treated and placebo-treated patients. In the LEADER trial , the incidence of cholelithiasis was 1.5% (3.9 cases per 1,000 patient years of observation) in adult VICTOZA-treated and 1.1% (2.8 cases per 1,000 patient years of observation) in placebo-treated patients, both on a background of standard of care.

The incidence of acute cholecystitis was 1.1% (2.9 cases per 1,000 patient years of observation) in adult VICTOZA-treated and 0.7% (1.9 cases per 1,000 patient years of observation) in placebo-treated patients. The majority of events required hospitalization or cholecystectomy. Laboratory Tests Bilirubin In the five adult glycemic control trials of at least 26 weeks duration, mildly elevated serum bilirubin concentrations (elevations to no more than twice the upper limit of the reference range) occurred in 4% of VICTOZA-treated patients, 2.1% of placebo-treated patients and 3.5% of active-comparator-treated patients.

This finding was not accompanied by abnormalities in other liver tests. The significance of this isolated finding is unknown. Calcitonin Calcitonin, a biological marker of MTC, was measured throughout the clinical development program. At the end of the adult glycemic control trials, adjusted mean serum calcitonin concentrations were higher in VICTOZA-treated patients compared to placebo-treated patients but not compared to patients receiving active comparator.

Between group differences in adjusted mean serum calcitonin values were approximately 0.1 ng/L or less. Among adult patients with pretreatment calcitonin <20 ng/L, calcitonin elevations to >20 ng/L occurred in 0.7% of VICTOZA-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown.

Lipase and Amylase In one adult glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for VICTOZA-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. In the LEADER trial, serum lipase and amylase were routinely measured. Among adult VICTOZA-treated patients, 7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the upper limit of normal compared with 4.5% of placebo-treated patients, and 1% of VICTOZA-treated patients had an amylase value at any time during treatment of greater than or equal to 3 times the upper limit of normal versus 0.7% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with VICTOZA is unknown in the absence of other signs and symptoms of pancreatitis . Vital signs VICTOZA did not have adverse effects on blood pressure.

Mean increases from baseline in heart rate of 2 to 3 beats per minute have been observed in adult patients treated with VICTOZA compared to placebo.

6.2Postmarketing Experience The

following additional adverse reactions have been reported during post-approval use of VICTOZA. 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. • 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: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis • Hypersensitivity: Angioedema, anaphylactic reactions, pruritus • Neoplasms: Medullary thyroid carcinoma • Neurologic: Dysgeusia, dizziness, dysesthesia • 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 renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine • Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia