Victoza Drug Information

Generic name: LIRAGLUTIDE

GLP-1 Receptor Agonist [EPC]

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Uses of Victoza

is indicated:
as an adjunct to diet and exercise to improve glycemic control in patients 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 [see Clinical Studies ( 14.3 )] . Limitations of Use : VICTOZA should not be used in patients with type 1 diabetes mellitus. VICTOZA contains liraglutide and should not be coadministered with other liraglutide-containing products. VICTOZA is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated:
as an adjunct to diet and exercise to improve glycemic control in patients 10 years and older with type 2 diabetes mellitus (1) .
to reduce the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease ( 1 ). Limitations of Use :
Not for treatment of type 1 diabetes mellitus.
Should not be coadministered with other liraglutide-containing products.

Dosage & Administration of Victoza

Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles ( 2.1 ).
Inject VICTOZA subcutaneously once-daily at any time of day, independently of meals, in the abdomen, thigh or upper arm ( 2.1 ).
When using VICTOZA with insulin, administer as separate injections. Never mix. ( 2.1 ).
Adult Dosage: Initiate at 0.6 mg 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 ( 2.2 ).
Pediatric Dosage: Initiate at 0.6 mg 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 ( 2.3 ). 2.1 Important Dosing and 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 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 ( 6.3 )].
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.
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 VICTOZA dose, reinitiate VICTOZA at 0.6 mg to mitigate any gastrointestinal symptoms associated with reinitiation of treatment. Upon reinitiation, VICTOZA should be titrated at the discretion of the prescriber. 2.2 Adult Dosage
Initiate VICTOZA with a dose of 0.6 mg daily for one week. The 0.6 mg dose is a starting dose intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control in adults. After one week at 0.6 mg per day, increase the dose to 1.2 mg daily.
If additional glycemic control is required, increase the dose to 1.8 mg daily after at least one week of treatment with the 1.2 mg daily dose. 2.3 Pediatric Dosage
Initiate VICTOZA with a dose of 0.6 mg daily.
After at least one week at 0.6 mg daily, the dose may be increased to 1.2 mg daily if additional glycemic control is required.
If additional glycemic control is required, increase the dose to 1.8 mg daily after at least one week of treatment with the 1.2 mg daily dose.

Side Effects of Victoza

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 )]
Pancreatitis [see Warnings and Precautions ( 5.2 )]
Hypoglycemia [see Warnings and Precautions ( 5.4 )]
Renal Impairment [see Warnings and Precautions ( 5.5 )]
Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )]
Acute Gallbladder Disease [see Warnings and Precautions ( 5.7 )]
The most common adverse reactions, reported in ≥5% of patients treated with VICTOZA are: nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation (6.1) .
Immunogenicity-related events, including urticaria, were more common among VICTOZA-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials (6.2) . 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of VICTOZA in subjects with type 2 diabetes 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 [see Clinical Studies ( 14.1 )] . The data in Table 1 reflect exposure of 1673 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 9.1 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88.1% and moderately impaired in 11.9% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of VICTOZA. 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 adolescents and children aged 10 years and above were comparable to that observed in the adult population. Table 1 Adverse reactions reported in ≥ 5% of VICTOZA-treated patients 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 clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of VICTOZA-treated patients and 0.5% of placebo-treated patients. Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials. Injection site reactions Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of VICTOZA-treated 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 1000 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 0.1 (0.001) Patient able to self-treat 2.5 (0.06) 3.6 (0.05) Add-on to Glimepiride Placebo + Glimepiride (N = 114) VICTOZA + Glimepiride (N = 695) Patient not able to self-treat 0 0.1 (0.003) Patient able to self-treat 2.6 (0.17) 7.5 (0.38) Not classified 0 0.9 (0.05) Add-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 (0.15) 7.9 (0.49) Not classified 1.1 (0.03) 0.6 (0.01) Add-on to Metformin + Glimepiride Placebo + Metformin + Glimepiride (N = 114) VICTOZA + Metformin + Glimepiride (N = 230) Patient not able to self-treat 0 2.2 (0.06) Patient able to self-treat 16.7 (0.95) 27.4 (1.16) Not 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 pediatric placebo-controlled clinical trial with a 26-week open-label extension, 21.2% of VICTOZA treated patients (mean age 14.6 years) with type 2 diabetes, had hypoglycemia with a blood glucose <54 mg/dL with or without symptoms (335 events per 1000 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 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 1000 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. Cholelithiasis and cholecystitis In 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 [see Clinical Studies ( 14.3 )] , the incidence of cholelithiasis was 1.5% (3.9 cases per 1000 patient years of observation) in VICTOZA-treated and 1.1% (2.8 cases per 1000 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 1000 patient years of observation) in VICTOZA-treated and 0.7% (1.9 cases per 1000 patient years of observation) in placebo-treated patients. The majority of events required hospitalization or cholecystectomy. Laboratory Tests Bilirubin In the five 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 4.0% 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 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 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 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 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 [see Warnings and Precautions ( 5.2 )]. 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 with VICTOZA compared to placebo. 6.2 Immunogenicity Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with VICTOZA may develop anti-liraglutide antibodies. 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 liraglutide cannot be directly compared with the incidence of antibodies of other products. Approximately 50-70% of VICTOZA-treated patients in five double-blind clinical trials of 26 weeks duration or longer were tested for the presence of anti-liraglutide antibodies at the end of treatment. Low titers (concentrations not requiring dilution of serum) of anti-liraglutide antibodies were detected in 8.6% of these VICTOZA-treated patients. Cross-reacting anti-liraglutide antibodies to native glucagon-like peptide-1 (GLP-1) occurred in 6.9% of the VICTOZA-treated patients in the double-blind 52-week monotherapy trial and in 4.8% of the VICTOZA-treated patients in the double-blind 26-week add-on combination therapy trials. These cross-reacting antibodies were not tested for neutralizing effect against native GLP-1, and thus the potential for clinically significant neutralization of native GLP-1 was not assessed. Antibodies that had a neutralizing effect on liraglutide in an in vitro assay occurred in 2.3% of the VICTOZA-treated patients in the double-blind 52-week monotherapy trial and in 1.0% of the VICTOZA-treated patients in the double-blind 26-week add-on combination therapy trials. Antibody formation was not associated with reduced efficacy of VICTOZA when comparing mean HbA1c of all antibody-positive and all antibody-negative patients. However, the 3 patients with the highest titers of anti-liraglutide antibodies had no reduction in HbA1c with VICTOZA treatment. In five double-blind glycemic control trials of VICTOZA, events from a composite of adverse events potentially related to immunogenicity (e.g., urticaria, angioedema) occurred among 0.8% of VICTOZA-treated patients and among 0.4% of comparator-treated patients. Urticaria accounted for approximately one-half of the events in this composite for VICTOZA-treated patients. Patients who developed anti-liraglutide antibodies were not more likely to develop events from the immunogenicity events composite than were patients who did not develop anti-liraglutide antibodies. In the LEADER trial [see Clinical Studies ( 14.3 )] , anti-liraglutide antibodies were detected in 11 out of the 1247 (0.9%) VICTOZA-treated patients with antibody measurements. Of the 11 VICTOZA-treated patients who developed anti-liraglutide antibodies, none were observed to develop neutralizing antibodies to liraglutide, and 5 patients (0.4%) developed cross-reacting antibodies against native GLP-1. In a clinical trial with pediatric patients 10 to 17 years [see Clinical Studies ( 14.2 )], anti-liraglutide antibodies were detected in 1 (1.5%) VICTOZA treated patient at week 26 and 5 (8.5%) VICTOZA treated patients at week 53. None of the 5 had antibodies cross reactive to native GLP-1 or had neutralizing antibodies. 6.3 Post-Marketing 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.
Medullary thyroid carcinoma
Dehydration resulting from nausea, vomiting and diarrhea.
Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis.
Angioedema and anaphylactic reactions.
Allergic reactions: rash and pruritus
Skin and subcutaneous tissue disorder: cutaneous amyloidosis
Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death
Hepatobiliary disorders: hyperbilirubinemia, elevations of liver enzymes, cholestasis, hepatitis, cholecystitis, cholelithiasis requiring cholecystectomy

Warnings & Cautions for Victoza

Thyroid C-cell Tumors : See Boxed Warning (5.1) .
Pancreatitis : Postmarketing reports, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed ( 5.2 ).
Never share a VICTOZA pen between patients, even if the needle is changed (5.3) .
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 (5.4) .
Renal Impairment : Postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration which may sometimes require hemodialysis. Use caution when initiating or escalating doses of VICTOZA in patients with renal impairment (5.5) .
Hypersensitivity : Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). Discontinue VICTOZA and promptly seek medical advice (5.6) .
Acute Gallbladder Disease : If cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated (5.7) . 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 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. 5.2 Pancreatitis Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with VICTOZA. After initiation of VICTOZA, 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, VICTOZA should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, VICTOZA should not be restarted. 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 1000 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. VICTOZA has been studied in a limited number of 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 VICTOZA. 5.3 Never 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. 5.4 Hypoglycemia 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. [see Adverse Reactions (6.1) , Drug Interactions (7.2) ]. 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. 5.5 Renal Impairment VICTOZA has not been found to be directly nephrotoxic in animal studies or clinical trials. There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in VICTOZA-treated patients [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, diarrhea, or dehydration [see Adverse Reactions ( 6.1 )] . Some of the reported events occurred in patients receiving one or more medications known to affect renal function or hydration status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including VICTOZA. Use caution when initiating or escalating doses of VICTOZA in patients with renal impairment [see Use in Specific Populations ( 8.6 )] . 5.6 Hypersensitivity 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. Do not use in patients with a previous hypersensitivity reaction to VICTOZA [see Contraindications ( 4 )] . 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. 5.7 Acute Gallbladder Disease Acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing. In the LEADER trial [see Clinical Studies ( 14.3 )], 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 [see Adverse Reactions ( 6.1 )] . If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated .

Drug Interactions with Victoza

Oral Medications

VICTOZA causes a delay of gastric emptying, and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials, VICTOZA did not affect the absorption of the tested orally administered medications to any clinically relevant degree. Nonetheless, caution should be exercised when oral medications are concomitantly administered with VICTOZA.

Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin

When initiating VICTOZA, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia.

Pregnancy Safety for Victoza

Pregnancy 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications.

Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Animal Data Female rats given subcutaneous doses of 0.1, 0.25 and 1.0 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 1.0 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.

Pediatric Use of Victoza

Pediatric Use The safety and effectiveness of VICTOZA as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients 10 years of age and older. Use of VICTOZA for this indication is supported by a 26-week placebo-controlled clinical trial and a 26-week open-label extension in 134 pediatric patients 10 to 17 years of age with type 2 diabetes, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus . The risk of hypoglycemia was higher with VICTOZA in pediatric patients regardless of insulin and/or metformin use. The safety and effectiveness of VICTOZA have not been established in pediatric patients less than 10 years of age.

Contraindications for Victoza

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) .

Overdosage Information for Victoza

Overdoses have been reported in clinical trials and post-marketing use of VICTOZA. Observed effects have included severe nausea, severe vomiting, and severe hypoglycemia. In the event of overdosage, appropriate supportive treatment should be initiated according to the patient’s clinical signs and symptoms.

Clinical Studies of Victoza

Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

In glycemic control trials, VICTOZA has been studied as monotherapy and in combination with one or two oral anti-diabetic medications or basal insulin. VICTOZA was also studied in a cardiovascular outcomes trial (LEADER trial). In each of the placebo controlled trials, treatment with VICTOZA produced clinically and statistically significant improvements in hemoglobin A 1c and fasting plasma glucose (FPG) compared to placebo. All VICTOZA-treated patients started at 0.6 mg/day.

The dose was increased in weekly intervals by 0.6 mg to reach 1.2 mg or 1.8 mg for patients randomized to these higher doses. VICTOZA 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance . Monotherapy In this 52-week trial, 746 patients were randomized to VICTOZA 1.2 mg, VICTOZA 1.8 mg, or glimepiride 8 mg. Patients who were randomized to glimepiride were initially treated with 2 mg daily for two weeks, increasing to 4 mg daily for another two weeks, and finally increasing to 8 mg daily.

Treatment with VICTOZA 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA 1c compared to glimepiride (Table 3). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the VICTOZA 1.8 mg treatment group, 6.0% in the VICTOZA 1.2 mg treatment group, and 10.1% in the glimepiride-treatment group. The mean age of participants was 53 years, and the mean duration of diabetes was 5 years. Participants were 49.7% male, 77.5% White, 12.6% Black or African American and 35.0% of Hispanic ethnicity.

The mean BMI was 33.1 kg/m 2. Table 3 Results of a 52-week monotherapy trial a VICTOZA 1.8 mg VICTOZA 1.2 mg Glimepiride 8 mg Intent-to-Treat Population (N) 246 251 248 HbA 1c (%) (Mean) Baseline 8.2 8.2

Change from baseline (adjusted mean) b -1.1 -0.8 -0.5 Difference from glimepiride

arm (adjusted mean) b -0.6** -0.3* 95% Confidence Interval (-0.8, -0.4) (-0.5, -0.1) Percentage of patients achieving HbA 1c <7% 51 43 28 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 172 168 172 Change from baseline (adjusted mean) b -26 -15 -5 Difference from glimepiride arm (adjusted mean) b -20** -10* 95% Confidence Interval (-29, -12) (-19, -1) Body Weight (kg) (Mean) Baseline 92.6 92.1

Change from baseline (adjusted mean) b -2.5 -2.1 +1.1 Difference from glimepiride

arm (adjusted mean) b -3.6** -3.2** 95% Confidence Interval (-4.3, -2.9) (-3.9, -2.5) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value *p-value <0.05 **p-value <0.0001 Figure 3 Mean HbA 1c for patients who completed the 52-week trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 52 (Monotherapy) Combination Therapy Add-on to Metformin In this 26-week trial, 1091 patients were randomized to VICTOZA 0.6 mg, VICTOZA 1.2 mg, VICTOZA 1.8 mg, placebo, or glimepiride 4 mg (one-half of the maximal approved dose in the United States), all as add-on to metformin. Randomization occurred after a 6-week run-in period consisting of a 3-week initial forced metformin titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin were increased up to 2000 mg/day.

Treatment with VICTOZA 1.2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA 1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA 1c reduction relative to glimepiride 4 mg add-on to metformin (Table 4). The percentage of patients who discontinued due to ineffective therapy was 5.4% in the VICTOZA 1.8 mg + metformin treatment group, 3.3% in the VICTOZA 1.2 mg + metformin treatment group, 23.8% in the placebo + metformin treatment group, and 3.7% in the glimepiride + metformin treated group. The mean age of participants was 57 years, and the mean duration of diabetes was 7 years. Participants were 58.2% male, 87.1% White and 2.4% Black or African American.

The mean BMI was 31.0 kg/m 2. Table 4 Results of a 26-week trial of VICTOZA as add-on to metformin a VICTOZA 1.8 mg + Metformin VICTOZA 1.2 mg + Metformin Placebo + Metformin Glimepiride 4 mg † + Metformin Intent-to-Treat Population (N) 242 240 121 242 HbA 1c (%) (Mean) Baseline 8.4 8.3 8.4

Change from baseline (adjusted mean) b -1.0 -1.0 +0.1 -1.0 Difference from

placebo + metformin arm (adjusted mean) b -1.1** -1.1** 95% Confidence Interval (-1.3, -0.9) (-1.3, -0.9) Difference from glimepiride + metformin arm (adjusted mean) b 0.0 0.0 95% Confidence Interval (-0.2, 0.2) (-0.2, 0.2) Percentage of patients achieving HbA 1c <7% 42 35 11 36 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 181 179 182 180 Change from baseline (adjusted mean) b -30 -30 +7 -24 Difference from placebo + metformin arm (adjusted mean) b -38** -37** 95% Confidence Interval (-48, -27) (-47, -26) Difference from glimepiride + metformin arm (adjusted mean) b -7 -6 95% Confidence Interval (-16, 2) (-15, 3) Body Weight (kg) (Mean) Baseline 88.0 88.5 91.0

Change from baseline (adjusted mean) b -2.8 -2.6 -1.5 +1.0 Difference from

placebo + metformin arm (adjusted mean) b 95% Confidence Interval -1.3* (-2.2, -0.4) -1.1* (-2.0, -0.2) Difference from glimepiride + metformin arm (adjusted mean) b -3.8** -3.5** 95% Confidence Interval (-4.5, -3.0) (-4.3, -2.8) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For glimepiride, one-half of the maximal approved United States dose. *p-value <0.05 **p-value <0.0001 VICTOZA Compared to Sitagliptin, Both as Add-on to Metformin In this 26–week, open-label trial, 665 patients on a background of metformin ≥1500 mg per day were randomized to VICTOZA 1.2 mg once-daily, VICTOZA 1.8 mg once-daily or sitagliptin 100 mg once-daily, all dosed according to approved labeling. Patients were to continue their current treatment on metformin at a stable, pre-trial dose level and dosing frequency. The mean age of participants was 56 years, and the mean duration of diabetes was 6 years.

Participants were 52.9% male, 86.6% White, 7.2% Black or African American and 16.2% of Hispanic ethnicity. The mean BMI was 32.8 kg/m 2. The primary endpoint was the change in HbA 1c from baseline to Week 26. Treatment with VICTOZA 1.2 mg and VICTOZA 1.8 mg resulted in statistically significant reductions in HbA 1c relative to sitagliptin 100 mg (Table 5). The percentage of patients who discontinued due to ineffective therapy was 3.1% in the VICTOZA 1.2 mg group, 0.5% in the VICTOZA 1.8 mg treatment group, and 4.1% in the sitagliptin 100 mg treatment group. From a mean baseline body weight of 94 kg, there was a mean reduction of 2.7 kg for VICTOZA 1.2 mg, 3.3 kg for VICTOZA 1.8 mg, and 0.8 kg for sitagliptin 100 mg.

Table 5 Results of a 26-week open-label trial of VICTOZA Compared to Sitagliptin (both in combination with metformin) a VICTOZA 1.8 mg + Metformin VICTOZA 1.2 mg + Metformin Sitagliptin 100 mg + Metformin Intent-to-Treat Population (N) 218 221 219 HbA 1c (%) (Mean) Baseline 8.4 8.4

Change from baseline (adjusted mean) -1.5 -1.2 -0.9 Difference from sitagliptin arm

(adjusted mean) b 95% Confidence Interval -0.6** (-0.8, -0.4) -0.3** (-0.5, -0.2) Percentage of patients achieving HbA 1c <7% 56 44 22 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 179 182 180 Change from baseline (adjusted mean) -39 -34 -15 Difference from sitagliptin arm (adjusted mean) b 95% Confidence Interval -24** (-31, -16) -19** (-26, -12) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value **p-value <0.0001 Figure 4 Mean HbA 1c for patients who completed the 26-week trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 26 Combination Therapy with Metformin and Insulin This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA 1c 7-10%) on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA 1c 7-8.5%) on metformin (≥1500 mg/day) and a sulfonylurea. Patients who were on metformin and a sulfonylurea discontinued the sulfonylurea then all patients entered a 12-week run-in period during which they received add-on therapy with VICTOZA titrated to 1.8 mg once-daily. At the end of the run-in period, 498 patients (50%) achieved HbA 1c <7% with VICTOZA 1.8 mg and metformin and continued treatment in a non-randomized, observational arm.

Another 167 patients (17%) withdrew from the trial during the run-in period with approximately one-half of these patients doing so because of gastrointestinal adverse reactions . The remaining 323 patients with HbA 1c ≥7% (33% of those who entered the run-in period) were randomized to 26 weeks of once-daily insulin detemir administered in the evening as add-on therapy (N=162) or to continued, unchanged treatment with VICTOZA 1.8 mg and metformin (N=161). The starting dose of insulin detemir was 10 units/day and the mean dose at the end of the 26-week randomized period was 39 units/day. During the 26 week randomized treatment period, the percentage of patients who discontinued due to ineffective therapy was 11.2% in the group randomized to continued treatment with VICTOZA 1.8 mg and metformin and 1.2% in the group randomized to add-on therapy with insulin detemir. The mean age of participants was 57 years, and the mean duration of diabetes was 8 years.

Participants were 55.7% male, 91.3% White, 5.6% Black or African American and 12.5% of Hispanic ethnicity. The mean BMI was 34.0 kg/m 2. Treatment with insulin detemir as add-on to VICTOZA 1.8 mg + metformin resulted in statistically significant reductions in HbA 1c and FPG compared to continued, unchanged treatment with VICTOZA 1.8 mg + metformin alone (Table 6). From a mean baseline body weight of 96 kg after randomization, there was a mean reduction of 0.3 kg in the patients who received insulin detemir add-on therapy compared to a mean reduction of 1.1 kg in the patients who continued on unchanged treatment with VICTOZA 1.8 mg + metformin alone. Table 6 Results of a 26-week open label trial of Insulin detemir as add on to VICTOZA + metformin compared to continued treatment with VICTOZA + metformin alone in patients not achieving HbA 1c < 7% after 12 weeks of Metformin and VICTOZA a Insulin detemir + VICTOZA + Metformin VICTOZA + Metformin Intent-to-Treat Population (N) 162 157 HbA 1c (%) (Mean) Baseline (week 0) 7.6

Change from baseline (adjusted mean) -0.5 0 Difference from

VICTOZA + metformin arm (LS mean) b -0.5** 95% Confidence Interval (-0.7, -0.4) Percentage of patients achieving HbA 1c <7% 43 17 Fasting Plasma Glucose (mg/dL) (Mean) Baseline (week 0) 166 159 Change from baseline (adjusted mean) -39 -7 Difference from VICTOZA + metformin arm (LS mean) b -31** 95% Confidence Interval (-39, -23) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value **p-value <0.0001 Add-on to Sulfonylurea In this 26-week trial, 1041 patients were randomized to VICTOZA 0.6 mg, VICTOZA 1.2 mg, VICTOZA 1.8 mg, placebo, or rosiglitazone 4 mg (one-half of the maximal approved dose in the United States), all as add-on to glimepiride. Randomization occurred after a 4-week run-in period consisting of an initial, 2-week, forced-glimepiride titration period followed by a maintenance period of another 2 weeks. During the titration period, doses of glimepiride were increased to 4 mg/day.

The doses of glimepiride could be reduced (at the discretion of the investigator) from 4 mg/day to 3 mg/day or 2 mg/day (minimum) after randomization, in the event of unacceptable hypoglycemia or other adverse events. The mean age of participants was 56 years, and the mean duration of diabetes was 8 years. Participants were 49.4% male, 64.4% White and 2.8% Black or African American.

The mean BMI was 29.9 kg/m 2. Treatment with VICTOZA 1.2 mg and 1.8 mg as add-on to glimepiride resulted in a statistically significant reduction in mean HbA 1c compared to placebo add-on to glimepiride (Table 7). The percentage of patients who discontinued due to ineffective therapy was 3.0% in the VICTOZA 1.8 mg + glimepiride treatment group, 3.5% in the VICTOZA 1.2 mg + glimepiride treatment group, 17.5% in the placebo + glimepiride treatment group, and 6.9% in the rosiglitazone + glimepiride treatment group. Table 7 Results of a 26-week trial of VICTOZA as add-on to sulfonylurea a VICTOZA 1.8 mg + Glimepiride VICTOZA 1.2 mg + Glimepiride Placebo + Glimepiride Rosiglitazone 4 mg † + Glimepiride Intent-to-Treat Population (N) 234 228 114 231 HbA 1c (%) (Mean) Baseline 8.5 8.5 8.4

Change from baseline (adjusted mean) b -1.1 -1.1 +0.2 -0.4 Difference from

placebo + glimepiride arm (adjusted mean) b -1.4** -1.3** 95% Confidence Interval (-1.6, -1.1) (-1.5, -1.1) Percentage of patients achieving HbA 1c <7% 42 35 7 22 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 174 177 171 179 Change from baseline (adjusted mean) b -29 -28 +18 -16 Difference from placebo + glimepiride arm (adjusted mean) b -47** -46** 95% Confidence Interval (-58, -35) (-58, -35) Body Weight (kg) (Mean) Baseline 83.0 80.0 81.9

Change from baseline (adjusted mean) b -0.2 +0.3 -0.1 +2.1 Difference from

placebo + glimepiride arm (adjusted mean) b -0.1 0.4 95% Confidence Interval (-0.9, 0.6) (-0.4, 1.2) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For rosiglitazone, one-half of the maximal approved United States dose. **p-value <0.0001 Add-on to Metformin and Sulfonylurea In this 26-week trial, 581 patients were randomized to VICTOZA 1.8 mg, placebo, or insulin glargine, all as add-on to metformin and glimepiride. Randomization took place after a 6-week run-in period consisting of a 3-week forced metformin and glimepiride titration period followed by a maintenance period of another 3 weeks. During the titration period, doses of metformin and glimepiride were to be increased up to 2000 mg/day and 4 mg/day, respectively.

After randomization, patients randomized to VICTOZA 1.8 mg underwent a 2 week period of titration with VICTOZA. During the trial, the VICTOZA and metformin doses were fixed, although glimepiride and insulin glargine doses could be adjusted. Patients titrated glargine twice-weekly during the first 8 weeks of treatment based on self-measured fasting plasma glucose on the day of titration. After Week 8, the frequency of insulin glargine titration was left to the discretion of the investigator, but, at a minimum, the glargine dose was to be revised, if necessary, at Weeks 12 and 18. Only 20% of glargine-treated patients achieved the pre-specified target fasting plasma glucose of ≤100 mg/dL. Therefore, optimal titration of the insulin glargine dose was not achieved in most patients.

The mean age of participants was 58 years, and the mean duration of diabetes was 9 years. Participants were 56.5% male, 75.0% White and 3.6% Black or African American. The mean BMI was 30.5 kg/m 2. Treatment with VICTOZA as add-on to glimepiride and metformin resulted in a statistically significant mean reduction in HbA 1c compared to placebo add-on to glimepiride and metformin (Table 8). The percentage of patients who discontinued due to ineffective therapy was 0.9% in the VICTOZA 1.8 mg + metformin + glimepiride treatment group, 0.4% in the insulin glargine + metformin + glimepiride treatment group, and 11.3% in the placebo + metformin + glimepiride treatment group.

Table 8 Results of a 26-week trial of VICTOZA as add-on to metformin and sulfonylurea a VICTOZA 1.8 mg + Metformin + Glimepiride Placebo + Metformin + Glimepiride Insulin glargine † + Metformin + Glimepiride Intent-to-Treat Population (N) 230 114 232 HbA 1c (%) (Mean) Baseline 8.3 8.3

Change from baseline (adjusted mean) b -1.3 -0.2 -1.1 Difference from placebo

+ metformin + glimepiride arm (adjusted mean) b -1.1** 95% Confidence Interval (-1.3, -0.9) Percentage of patients achieving HbA 1c <7% 53 15 46 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 165 170 164 Change from baseline (adjusted mean) b -28 +10 -32 Difference from placebo + metformin + glimepiride arm (adjusted mean) b -38** 95% Confidence Interval (-46, -30) Body Weight (kg) (Mean) Baseline 85.8 85.4

Change from baseline (adjusted mean) b -1.8 -0.4 1.6 Difference from placebo

+ metformin + glimepiride arm (adjusted mean) b -1.4* 95% Confidence Interval (-2.1, -0.7) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value † For insulin glargine, optimal titration regimen was not achieved for 80% of patients. *p-value <0.05 **p-value <0.0001 VICTOZA Compared to Exenatide, Both as Add-on to Metformin and/or Sulfonylurea Therapy In this 26–week, open-label trial, 464 patients on a background of metformin monotherapy, sulfonylurea monotherapy or a combination of metformin and sulfonylurea were randomized to once daily VICTOZA 1.8 mg or exenatide 10 mcg twice daily. Maximally tolerated doses of background therapy were to remain unchanged for the duration of the trial. Patients randomized to exenatide started on a dose of 5 mcg twice-daily for 4 weeks and then were escalated to 10 mcg twice daily.

The mean age of participants was 57 years, and the mean duration of diabetes was 8 years. Participants were 51.9% male, 91.8% White, 5.4% Black or African American and 12.3% of Hispanic ethnicity. The mean BMI was 32.9 kg/m 2. Treatment with VICTOZA 1.8 mg resulted in statistically significant reductions in HbA 1c and FPG relative to exenatide (Table 9). The percentage of patients who discontinued for ineffective therapy was 0.4% in the VICTOZA treatment group and 0% in the exenatide treatment group.

Both treatment groups had a mean decrease from baseline in body weight of approximately 3 kg. Table 9 Results of a 26-week open-label trial of VICTOZA versus Exenatide (both in combination with metformin and/or sulfonylurea) a VICTOZA 1.8 mg once daily + metformin and/or sulfonylurea Exenatide 10 mcg twice daily + metformin and/or sulfonylurea Intent-to-Treat Population (N) 233 231 HbA 1c (%) (Mean) Baseline 8.2

Change from baseline (adjusted mean) b -1.1 -0.8 Difference from exenatide arm

(adjusted mean) b 95% Confidence Interval -0.3** (-0.5, -0.2) Percentage of patients achieving HbA 1c <7% 54 43 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 176 171 Change from baseline (adjusted mean) b -29 -11 Difference from exenatide arm (adjusted mean) b 95% Confidence Interval -18** (-25, -12) a Intent-to-treat population using last observation carried forward b Least squares mean adjusted for baseline value **p-value <0.0001 Add-on to Metformin and Thiazolidinedione In this 26-week trial, 533 patients were randomized to VICTOZA 1.2 mg, VICTOZA 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2000 mg). Patients underwent a 9 week run-in period (3-week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with increasing weekly increments of 500 mg to a final dose of 2000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial. The mean age of participants was 55 years, and the mean duration of diabetes was 9 years. Participants were 61.6% male, 84.2% White, 10.2% Black or African American and 16.4% of Hispanic ethnicity.

The mean BMI was 33.9 kg/m 2. Treatment with VICTOZA as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA 1c compared to placebo add-on to metformin and rosiglitazone (Table 10). The percentage of patients who discontinued due to ineffective therapy was 1.7% in the VICTOZA 1.8 mg + metformin + rosiglitazone treatment group, 1.7% in the VICTOZA 1.2 mg + metformin + rosiglitazone treatment group, and 16.4% in the placebo + metformin + rosiglitazone treatment group. Table 10 Results of a 26-week trial of VICTOZA as add-on to metformin and thiazolidinedione a VICTOZA 1.8 mg + Metformin + Rosiglitazone VICTOZA 1.2 mg + Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone Intent-to-Treat Population (N) 178 177 175 HbA 1c (%) (Mean) Baseline 8.6 8.5

Change from baseline (adjusted mean) b -1.5 -1.5 -0.5 Difference from placebo

+ metformin + rosiglitazone arm (adjusted mean) b -0.9** -0.9** 95% Confidence Interval (-1.1, -0.8) (-1.1, -0.8) Percentage of patients achieving HbA 1c <7% 54 57 28 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 185 181 179 Change from baseline (adjusted mean) b -44 -40 -8 Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b -36** -32** 95% Confidence Interval (-44, -27) (-41, -23) Body Weight (kg) (Mean) Baseline 94.9 95.3

Change from baseline (adjusted mean) b -2.0 -1.0 +0.6 Difference from placebo

+ metformin + rosiglitazone arm (adjusted mean) b -2.6** -1.6** 95% Confidence Interval (-3.4, -1.8) (-2.4, -1.0) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value **p-value <0.0001 VICTOZA Compared to Placebo Both With or Without metformin and/or Sulfonylurea and/or Pioglitazone and/or Basal or Premix insulin in Patients with Type 2 Diabetes Mellitus and Moderate Renal Impairment In this 26-week, double-blind, randomized, placebo-controlled, parallel-group trial, 279 patients with moderate renal impairment, as per MDRD formula (eGFR 30−59 mL/min/1.73 m 2 ), were randomized to VICTOZA or placebo once daily. VICTOZA was added to the patient’s stable pre-trial antidiabetic regimen (insulin therapy and/or metformin, pioglitazone, or sulfonylurea). The dose of VICTOZA was escalated according to approved labeling to achieve a dose of 1.8 mg per day. The insulin dose was reduced by 20% at randomization for patients with baseline HbA 1c ≤ 8% and fixed until liraglutide dose escalation was complete.

Dose reduction of insulin and SU was allowed in case of hypoglycemia; up titration of insulin was allowed but not beyond the pre-trial dose. The mean age of participants was 67 years, and the mean duration of diabetes was 15 years. Participants were 50.5% male, 92.3% White, 6.6% Black or African American, and 7.2% of Hispanic ethnicity.

The mean BMI was 33.9 kg/m 2. Approximately half of patients had an eGFR between 30 and <45mL/min/1.73 m 2. Treatment with VICTOZA resulted in a statistically significant reduction in HbA 1c from baseline at Week 26 compared to placebo (see Table 11). 123 patients reached the 1.8 mg dose of VICTOZA. Table 11 Results of a 26-week trial of VICTOZA compared to placebo in Patients with Renal Impairment a VICTOZA 1.8 mg + insulin and/or OAD Placebo + insulin and/or OAD Intent to Treat Population (N) 140 137 HbA 1c (%) Baseline (mean) 8.1

Change from baseline (estimated mean) b, c -0.9 -0.4 Difference from placebo

b, c 95% Confidence Interval -0.6* (-0.8, -0.3) Proportion achieving HbA 1c < 7% d 39.3

FPG (mg/dL) Baseline (mean) 171 167 Change from baseline (estimated mean) e

-22 -10 Difference from placebo e 95% Confidence Interval -12** (-23, -0.8) a Intent-to-treat population b Estimated using a mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit. Multiple imputation method modeled “wash out” of the treatment effect for patients having missing data who discontinued treatment. c Early treatment discontinuation, before week 26, occurred in 25% and 22% of VICTOZA and placebo patients, respectively. d Based on the known number of subjects achieving HbA 1c < 7%. When applying the multiple imputation method described in b) above, the estimated percents achieving HbA 1c < 7% are 47.6% and 24.9% for VICTOZA and placebo, respectively. e Estimated using a mixed model for repeated measurement with treatment, country, stratification groups as factors and baseline as a covariate, all nested within visit. *p-value <0.0001 **p-value <0.05 Figure 3 Figure 4 Mean HbA1c for patients who completed the 26-week trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) data at Week 26

Glycemic Control Trial in Pediatric Patients 10 Years of Age and Older

with Type 2 Diabetes Mellitus VICTOZA was evaluated in a 26-week, double-blind, randomized, parallel group, placebo controlled multi-center trial (NCT01541215), in 134 pediatric patients with type 2 diabetes aged 10 years and older. Patients were randomized to VICTOZA once-daily or placebo once-daily in combination with metformin with or without basal insulin treatment. All patients were on a metformin dose of 1000 to 2000 mg prior to randomization.

The basal insulin dose was decreased by 20% at randomization and VICTOZA was titrated weekly by 0.6 mg for 2 to 3 weeks based on tolerability and an average fasting plasma glucose goal of < 110 mg/dL. The mean age was 14.6 years: 29.9% were ages 10-14 years, and 70.1% were greater than 14 years of age. 38.1% were male, 64.9% were White, 13.4% were Asian, 11.9% were Black or African American; 29.1% were of Hispanic or Latino ethnicity. The mean BMI was 33.9 kg/m 2 and the mean BMI SDS was 2.9. 18.7% of patients were using basal insulin at baseline. The mean duration of diabetes was 1.9 years and the mean HbA 1c was 7.8%. At week 26, treatment with VICTOZA was superior in reducing HbA 1c from baseline versus placebo.

The estimated treatment difference in HbA 1c reduction from baseline between VICTOZA and placebo was -1.06% with a 95% confidence interval of (see Table 12). Table 12 Results at week 26 in a trial comparing VICTOZA in combination with metformin with or without basal insulin versus Placebo in combination with metformin with or without basal insulin in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus VICTOZA+metformin±basal insulin Placebo+metformin±basal insulin N 66 68 HbA 1c (%) Baseline 7.9

End of 26 weeks 7.1 8.2 Adjusted mean change from baseline after

26 weeks a -0.64 0.42 Treatment difference VICTOZA vs Placebo -1.06 * Percentage of patients achieving HbA 1c <7% b 63.7

FPG (mg/dL) Baseline 157 147 End of 26 weeks 132 166 Adjusted

mean change from baseline after 26 weeks a -19.4

Treatment difference

VICTOZA vs Placebo -33.83 a The change from baseline to end of treatment visit in HbA 1c and FPG was analyzed using a pattern mixture model with multiple imputation. Missing observations (10.6% in the VICTOZA, 14.5% in the placebo) were imputed from the placebo arm based on multiple (x10,000) imputations. The data for week 26 was then analyzed with an ANCOVA model containing treatment, sex and age group as fixed effects and baseline value as covariate. b Categories are derived from continuous measurements of HbA 1c using a pattern mixture model with multiple imputation for missing observations. * p-value <0.001

Cardiovascular Outcomes Trial in Patients with Type 2 Diabetes Mellitus and Atherosclerotic

Cardiovascular Disease The LEADER trial (NCT01179048) was a multi-national, multi-center, placebo-controlled, double-blind trial. In this study, 9340 patients with inadequately controlled type 2 diabetes and atherosclerotic cardiovascular disease were randomized to VICTOZA 1.8 mg or placebo for a median duration of 3.5 years. The study compared the risk of major adverse cardiovascular events between VICTOZA and placebo when these were added to, and used concomitantly with, background standard of care treatments for type 2 diabetes.

The primary endpoint, MACE, was the time to first occurrence of a three part composite outcome which included; cardiovascular death, non-fatal myocardial infarction and non-fatal stroke. Patients eligible to enter the trial were; 50 years of age or older and had established, stable, cardiovascular, cerebrovascular, peripheral artery disease, chronic kidney disease or NYHA class II and III heart failure (80% of the enrolled population) or were 60 years of age or older and had other specified risk factors for cardiovascular disease (20% of the enrolled population). At baseline, demographic and disease characteristics were balanced. The mean age was 64 years and the population was 64.3% male, 77.5% Caucasian, 10.0% Asian, and 8.3% Black.

In the study, 12.1% of the population identified as Hispanic or Latino. The mean duration of type 2 diabetes was 12.8 years, the mean HbA1c was 8.7% and the mean BMI was 32.5 kg/m 2. A history of previous myocardial infarction was reported in 31% of randomized individuals, a prior revascularization procedure in 39%, a prior ischemic stroke in 11%, documented symptomatic coronary disease in 9%, documented asymptomatic cardiac ischemia in 26%, and a diagnosis of New York Heart Association (NYHA) class II to III heart failure in 14%. The mean eGFR at baseline was 79 mL/min/1.73 m 2 and 41.8% of patients had mild renal impairment (eGFR 60 to 90 mL/min/1.73m 2 ), 20.7% had moderate renal impairment (eGFR 30 to 60 mL/min/1.73m 2 ) and 2.4% of patients had severe renal impairment (eGFR < 30 mL/min/1.73m 2 ). At baseline, patients treated their diabetes with; diet and exercise only (3.9%), oral antidiabetic drugs only (51.5%), oral antidiabetic drugs and insulin (36.7%) or insulin only (7.9%). The most common background antidiabetic drugs used at baseline and in the trial were metformin, sulfonylurea and insulin. Use of DPP-4 inhibitors and other GLP-1 receptor agonists was excluded by protocol and SGLT-2 inhibitors were either not approved or not widely available.

At baseline, cardiovascular disease and risk factors were managed with; non-diuretic antihypertensives (92.4%), diuretics (41.8%), statin therapy (72.1%) and platelet aggregation inhibitors (66.8%). During the trial, investigators could modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets with respect to blood glucose, lipid, and blood pressure, and manage patients recovering from an acute coronary syndrome or stroke event per local treatment guidelines. For the primary analysis, a Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and to test for superiority on MACE if non-inferiority was demonstrated. Type 1 error was controlled across multiple tests.

VICTOZA significantly reduced the occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.87. Refer to Figure 5 and Table 13. Vital status was available for 99.7% of subjects in the trial. A total of 828 deaths were recorded during the LEADER trial. A majority of the deaths in the trial were categorized as cardiovascular deaths and non-cardiovascular deaths were balanced between the treatment groups (3.5% in patients treated with VICTOZA and 3.6% in patients treated with placebo). The estimated hazard ratio of time to all-cause death for VICTOZA compared to placebo was 0.85. Figure 5 Kaplan-Meier: Time to First Occurrence of a MACE in the LEADER Trial (Patients with T2DM and Atherosclerotic CVD) Table 13 Treatment Effect for the Primary Composite Endpoint, MACE, and its Components in the LEADER Trial (Patients with T2DM and Atherosclerotic CVD) a VICTOZA N=4668 Placebo N=4672 Hazard Ratio (95% CI) b Composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke (MACE) (time to first occurrence) c 608 (13.0%) 694 (14.9%) 0.87 (0.78; 0.97) Non-fatal myocardial infarction d 281 (6.0%) 317 (6.8%) 0.88 (0.75;1.03) Non-fatal stroke d 159 (3.4%) 177 (3.8%) 0.89 (0.72;1.11) Cardiovascular death d 219 (4.7%) 278 (6%) 0.78 (0.66;0.93) a Full analysis set (all randomized patients) b Cox-proportional hazards model with treatment as a factor c p-value for superiority (2-sided) 0.011 d Number and percentage of first events Figure 5

Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.

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