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Generic Name: liraglutide
Dosage Form: injection

WARNING: RISK OF THYROID C-CELL TUMORS
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether Victoza causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined [see Warnings and Precautions (5.1) and Nonclinical Toxicology (13.1)].
Victoza is contraindicated in patients with a personal or family history of MTC and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk 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 [see Contraindications (4) and Warnings and Precautions (5.1)].

Indications and Usage for Victoza

Victoza is indicated:

• as an adjunct to diet and exercise to improve glycemic control in adults 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 (14.2)].

Limitations of Use:

Victoza is not a substitute for insulin. Victoza should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.
The concurrent use of Victoza and prandial insulin has not been studied.

Victoza Dosage and Administration

Important Administration Instructions

Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles.
Inject Victoza subcutaneously in the abdomen, thigh or upper arm. No dose adjustment is needed if changing the injection site and/or timing.
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.

General Dosing and Administration

Inject Victoza subcutaneously once-daily at any time of day, independently of meals.
Initiate Victoza with a dose of 0.6 mg per day 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. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. 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 in 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.

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) to reduce the risk of hypoglycemia [see Warnings and Precautions (5.4) and Adverse Reactions (6)].

Dosage in Patients with Renal Impairment

No dose adjustment is recommended for patients with renal impairment.

Dosage Forms and Strengths

Injection: 6 mg/mL solution in a pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg.

Contraindications

Medullary Thyroid Carcinoma

Victoza is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

Hypersensitivity

Victoza is contraindicated in patients with a prior serious hypersensitivity reaction to Victoza or to any of the product components. Serious hypersensitivity reactions including anaphylactic reactions and angioedema have been reported with Victoza [see Warnings and Precautions (5.6)].

Warnings and Precautions

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.

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.

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.

Use with Medications Known to Cause Hypoglycemia

Patients receiving Victoza in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia. The risk of hypoglycemia may be lowered by a reduction in the dose of sulfonylurea (or other concomitantly administered insulin secretagogues) or insulin [see Dosage and Administration (2.2),Adverse Reactions (6.1)].

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

In the LEADER trial [see Clinical Studies (14.2)], 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. The majority of events required hospitalization or cholecystectomy. If cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.

Adverse Reactions

The following serious adverse reactions are described below or elsewhere in the prescribing information:

Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
Pancreatitis [see Warnings and Precautions (5.2)]
Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.4)]
Renal Impairment [see Warnings and Precautions (5.5)]
Hypersensitivity Reactions [see Warnings and Precautions (5.6)]

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 data in Table 1 are derived from 5 glycemic control, placebo-controlled trials [see Clinical Studies (14.1)]. These data reflect exposure of 1673 patients to Victoza and a mean duration of exposure to Victoza of 37.3 weeks. The mean age of 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 HbA1c 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, 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.

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

Hypoglycemia requiring the assistance of another person in placebo-controlled trials

In 5 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 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.

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 (14.2)], 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.

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.

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 (14.2)], 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.

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 [see Warnings and Precautions (5.1)]
Dehydration resulting from nausea, vomiting and diarrhea. [see Warnings and Precautions (5.5) and Patient Counseling Information (17)]
Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis. [see Warnings and Precautions (5.5) and Patient Counseling Information (17)]
Angioedema and anaphylactic reactions. [see Contraindications (4), Warnings and Precautions (5.6), Patient Counseling Information (17)]
Allergic reactions: rash and pruritus
Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see Warnings and Precautions (5.2)]
Hepatobiliary disorders: elevations of liver enzymes, hyperbilirubinemia, cholestasis, hepatitis [see Adverse Reactions (6.1)]

Drug Interactions

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.

USE IN SPECIFIC POPULATIONS

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 [see Animal Data].

The estimated background risk of major birth defects for women with uncontrolled pre-gestational diabetes (Hemoglobin A1C >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 A1C >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, stillbirth and delivery complications due to fetal macrosomia (e.g., perineal injury and lacerations, need for cesarean section, and post-partum hemorrhage). Poorly controlled diabetes increases the fetal risk for neural tube defects, cardiovascular malformations, oral clefts, still birth, macrosomia related morbidity (e.g., brachial plexus injury, hypoxia), and neonatal hyperglycemia.

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 F2 generation rats descended from liraglutide-treated rats compared to F2 generation rats descended from controls, but differences did not reach statistical significance for any group.

Lactation

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 [see Data].

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.

Pediatric Use

Safety and effectiveness of Victoza have not been established in pediatric patients. Victoza is not recommended for use in pediatric patients.

Geriatric Use

In the Victoza treatment arms of the glycemic control trials, a total of 832 (19.3%) of the patients were 65 to 74 years of age and 145 (3.4%) were 75 years of age and over. No overall differences in safety or efficacy were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

In the Victoza treatment arm of the LEADER trial [see Clinical Studies (14.2)], a total of 1738 (37.2%) patients were 65 to 74 years of age, 401 (8.6%) were 75 to 84 years of age, and 17 (0.4%) were 85 years of age or older at baseline. No overall differences in safety or efficacy were observed between these patients and younger patients.

Renal Impairment

No dose adjustment of Victoza is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)]. The safety and efficacy of Victoza was evaluated in a 26-week clinical study that included patients with moderate renal impairment (eGFR 30 to 60 mL/min/1.73m2) [see Clinical Studies (14.1)].

In the Victoza treatment arm of the LEADER trial [see Clinical Studies (14.2)], 1932 (41.4%) patients had mild renal impairment, 999 (21.4%) patients had moderate renal impairment and 117 (2.5%) patients had severe renal impairment at baseline. No overall differences in safety or efficacy were seen in these patients compared to patients with normal renal function.

There is limited experience with Victoza in patients with end stage renal disease.There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis [see Warnings and Precautions (5.5) and Adverse Reactions (6.2)]. Use caution in patients who experience dehydration.

Hepatic Impairment

There is limited experience in patients with mild, moderate or severe hepatic impairment. Therefore, Victoza should be used with caution in this patient population. No dose adjustment of Victoza is recommended for patients with hepatic impairment [see Clinical Pharmacology (12.3)].

Gastroparesis

Victoza slows gastric emptying. Victoza has not been studied in patients with pre-existing gastroparesis.

Overdosage

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

Victoza Description

Victoza contains liraglutide, an analog of human GLP-1 and acts as a GLP-1 receptor agonist. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae, has been engineered to be 97% homologous to native human GLP-1 by substituting arginine for lysine at position 34. Liraglutide is made by attaching a C-16 fatty acid (palmitic acid) with a glutamic acid spacer on the remaining lysine residue at position 26 of the peptide precursor. The molecular formula of liraglutide is C172H265N43O51 and the molecular weight is 3751.2 Daltons. The structural formula (Figure 1) is:

Figure 1 Structural Formula of liraglutide

Victoza is a clear, colorless or almost colorless solution. Each 1 mL of Victoza solution contains 6 mg of liraglutide and the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14 mg; phenol, 5.5 mg; and water for injection. Each pre-filled pen contains a 3 mL solution of Victoza equivalent to 18 mg liraglutide (free-base, anhydrous).

Victoza - Clinical Pharmacology

Mechanism of Action

Liraglutide is an acylated human Glucagon-Like Peptide-1 (GLP-1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP-1(7-37). GLP-1(7-37) represents <20% of total circulating endogenous GLP-1. Like GLP-1(7-37), liraglutide activates the GLP-1 receptor, a membrane-bound cell-surface receptor coupled to adenylyl cyclase by the stimulatory G-protein, Gs, in pancreatic beta cells. Liraglutide increases intracellular cyclic AMP (cAMP) leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Liraglutide also decreases glucagon secretion in a glucose-dependent manner. The mechanism of blood glucose lowering also involves a delay in gastric emptying.

GLP-1(7-37) has a half-life of 1.5-2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidases (NEP). Unlike native GLP-1, liraglutide is stable against metabolic degradation by both peptidases and has a plasma half-life of 13 hours after subcutaneous administration. The pharmacokinetic profile of liraglutide, which makes it suitable for once daily administration, is a result of self-association that delays absorption, plasma protein binding and stability against metabolic degradation by DPP-IV and NEP.

Pharmacodynamics

Victoza’s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as Victoza lowered fasting, premeal and postprandial glucose throughout the day [see Clinical Pharmacology (12.3)].

Fasting and postprandial glucose was measured before and up to 5 hours after a standardized meal after treatment to steady state with 0.6, 1.2 and 1.8 mg Victoza or placebo. Compared to placebo, the postprandial plasma glucose AUC0-300min was 35% lower after Victoza 1.2 mg and 38% lower after Victoza 1.8 mg.

Glucose-dependent insulin secretion

The effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) Victoza on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes during graded glucose infusion. In these patients, on average, the ISR response was increased in a glucose-dependent manner (Figure 2).

Figure 2 Mean Insulin Secretion Rate (ISR) versus Glucose Concentration Following Single-Dose Victoza 7.5 mcg/kg (~ 0.7 mg) or Placebo in Patients with Type 2 Diabetes (N=10) During Graded Glucose Infusion

Glucagon secretion

Victoza lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of Victoza 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations.

Gastric emptying

Victoza causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Cardiac Electrophysiology (QTc)

The effect of Victoza on cardiac repolarization was tested in a QTc study. Victoza at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation.

Pharmacokinetics

Absorption - Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8-12 hours post dosing. The mean peak (Cmax) and total (AUC) exposures of liraglutide were 35 ng/mL and 960 ng·h/mL, respectively, for a subcutaneous single dose of 0.6 mg. After subcutaneous single dose administrations, Cmax and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg. At 1.8 mg Victoza, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC0-∞ was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC0-∞ from thigh was 22% lower than that from abdomen. However, liraglutide exposures were considered comparable among these three subcutaneous injection sites. Absolute bioavailability of liraglutide following subcutaneous administration is approximately 55%.

Distribution - The mean apparent volume of distribution after subcutaneous administration of Victoza 0.6 mg is approximately 13 L. The mean volume of distribution after intravenous administration of Victoza is 0.07 L/kg. Liraglutide is extensively bound to plasma protein (>98%).

Metabolism - During the initial 24 hours following administration of a single [3H]-liraglutide dose to healthy subjects, the major component in plasma was intact liraglutide. Liraglutide is endogenously metabolized in a similar manner to large proteins without a specific organ as a major route of elimination.

Elimination - Following a [3H]-liraglutide dose, intact liraglutide was not detected in urine or feces. Only a minor part of the administered radioactivity was excreted as liraglutide-related metabolites in urine or feces (6% and 5%, respectively). The majority of urine and feces radioactivity was excreted during the first 6-8 days. The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately 1.2 L/h with an elimination half-life of approximately 13 hours, making Victoza suitable for once daily administration.

Specific Populations

Elderly - Age had no effect on the pharmacokinetics of Victoza based on a pharmacokinetic study in healthy elderly subjects (65 to 83 years) and population pharmacokinetic analyses of patients 18 to 80 years of age [see Use in Specific Populations (8.5)].

Gender - Based on the results of population pharmacokinetic analyses, females have 25% lower weight-adjusted clearance of Victoza compared to males. Based on the exposure response data, no dose adjustment is necessary based on gender.

Race and Ethnicity - Race and ethnicity had no effect on the pharmacokinetics of Victoza based on the results of population pharmacokinetic analyses that included Caucasian, Black, Asian and Hispanic/Non-Hispanic subjects.

Body Weight - Body weight significantly affects the pharmacokinetics of Victoza based on results of population pharmacokinetic analyses. The exposure of liraglutide decreases with an increase in baseline body weight. However, the 1.2 mg and 1.8 mg daily doses of Victoza provided adequate systemic exposures over the body weight range of 40 – 160 kg evaluated in the clinical trials. Liraglutide was not studied in patients with body weight >160 kg.

Pediatric - Victoza has not been studied in pediatric patients [see Use in Specific Populations (8.4)].

Renal Impairment - The single-dose pharmacokinetics of Victoza were evaluated in subjects with varying degrees of renal impairment. Subjects with mild (estimated creatinine clearance 50-80 mL/min) to severe (estimated creatinine clearance <30 mL/min) renal impairment and subjects with end-stage renal disease requiring dialysis were included in the trial. Compared to healthy subjects, liraglutide AUC in mild, moderate, and severe renal impairment and in end-stage renal disease was on average 35%, 19%, 29% and 30% lower, respectively [see Use in Specific Populations (8.6)].

Hepatic Impairment - The single-dose pharmacokinetics of Victoza were evaluated in subjects with varying degrees of hepatic impairment. Subjects with mild (Child Pugh score 5-6) to severe (Child Pugh score > 9) hepatic impairment were included in the trial. Compared to healthy subjects, liraglutide AUC in subjects with mild, moderate and severe hepatic impairment was on average 11%, 14% and 42% lower, respectively [see Use in Specific Populations (8.7)].

Drug Interactions

In vitro assessment of drug-drug interactions

Victoza has low potential for pharmacokinetic drug-drug interactions related to cytochrome P450 (CYP) and plasma protein binding.

In vivo assessment of drug-drug interactions

The drug-drug interaction studies were performed at steady state with Victoza 1.8 mg/day. Before administration of concomitant treatment, subjects underwent a 0.6 mg weekly dose increase to reach the maximum dose of 1.8 mg/day. Administration of the interacting drugs was timed so that Cmax of Victoza (8-12 h) would coincide with the absorption peak of the co-administered drugs.

Digoxin

A single dose of digoxin 1 mg was administered 7 hours after the dose of Victoza at steady state. The concomitant administration with Victoza resulted in a reduction of digoxin AUC by 16%; Cmax decreased by 31%. Digoxin median time to maximal concentration (Tmax) was delayed from 1 h to 1.5 h.

Lisinopril

A single dose of lisinopril 20 mg was administered 5 minutes after the dose of Victoza at steady state. The co-administration with Victoza resulted in a reduction of lisinopril AUC by 15%; Cmax decreased by 27%. Lisinopril median Tmax was delayed from 6 h to 8 h with Victoza.

Atorvastatin

Victoza did not change the overall exposure (AUC) of atorvastatin following a single dose of atorvastatin 40 mg, administered 5 hours after the dose of Victoza at steady state. Atorvastatin Cmax was decreased by 38% and median Tmax was delayed from 1 h to 3 h with Victoza.

Acetaminophen

Victoza did not change the overall exposure (AUC) of acetaminophen following a single dose of acetaminophen 1000 mg, administered 8 hours after the dose of Victoza at steady state. Acetaminophen Cmax was decreased by 31% and median Tmax was delayed up to 15 minutes.

Griseofulvin

Victoza did not change the overall exposure (AUC) of griseofulvin following co-administration of a single dose of griseofulvin 500 mg with Victoza at steady state. Griseofulvin Cmax increased by 37% while median Tmax did not change.

Oral Contraceptives

A single dose of an oral contraceptive combination product containing 0.03 mg ethinylestradiol and 0.15 mg levonorgestrel was administered under fed conditions and 7 hours after the dose of Victoza at steady state. Victoza lowered ethinylestradiol and levonorgestrel Cmax by 12% and 13%, respectively. There was no effect of Victoza on the overall exposure (AUC) of ethinylestradiol. Victoza increased the levonorgestrel AUC0-∞ by 18%. Victoza delayed Tmax for both ethinylestradiol and levonorgestrel by 1.5 h.

Insulin Detemir

No pharmacokinetic interaction was observed between Victoza and insulin detemir when separate subcutaneous injections of insulin detemir 0.5 Unit/kg (single-dose) and Victoza 1.8 mg (steady state) were administered in patients with type 2 diabetes.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week carcinogenicity study was conducted in male and female CD-1 mice at doses of 0.03, 0.2, 1.0, and 3.0 mg/kg/day liraglutide administered by bolus subcutaneous injection yielding systemic exposures 0.2-, 2-, 10- and 45-times the human exposure, respectively, at the MRHD of 1.8 mg/day based on plasma AUC comparison. A dose-related increase in benign thyroid C-cell adenomas was seen in the 1.0 and the 3.0 mg/kg/day groups with incidences of 13% and 19% in males and 6% and 20% in females, respectively. C-cell adenomas did not occur in control groups or 0.03 and 0.2 mg/kg/day groups. Treatment-related malignant C-cell carcinomas occurred in 3% of females in the 3.0 mg/kg/day group. Thyroid C-cell tumors are rare findings during carcinogenicity testing in mice. A treatment-related increase in fibrosarcomas was seen on the dorsal skin and subcutis, the body surface used for drug injection, in males in the 3 mg/kg/day group. These fibrosarcomas were attributed to the high local concentration of drug near the injection site. The liraglutide concentration in the clinical formulation (6 mg/mL) is 10-times higher than the concentration in the formulation used to administer 3 mg/kg/day liraglutide to mice in the carcinogenicity study (0.6 mg/mL).

A 104-week carcinogenicity study was conducted in male and female Sprague Dawley rats at doses of 0.075, 0.25 and 0.75 mg/kg/day liraglutide administered by bolus subcutaneous injection with exposures 0.5-, 2- and 8-times the human exposure, respectively, resulting from the MRHD based on plasma AUC comparison. A treatment-related increase in benign thyroid C-cell adenomas was seen in males in 0.25 and 0.75 mg/kg/day liraglutide groups with incidences of 12%, 16%, 42%, and 46% and in all female liraglutide-treated groups with incidences of 10%, 27%, 33%, and 56% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. A treatment-related increase in malignant thyroid C-cell carcinomas was observed in all male liraglutide-treated groups with incidences of 2%, 8%, 6%, and 14% and in females at 0.25 and 0.75 mg/kg/day with incidences of 0%, 0%, 4%, and 6% in 0 (control), 0.075, 0.25, and 0.75 mg/kg/day groups, respectively. Thyroid C-cell carcinomas are rare findings during carcinogenicity testing in rats.

Studies in mice demonstrated that liraglutide-induced C-cell proliferation was dependent on the GLP-1 receptor and that liraglutide did not cause activation of the REarranged during Transfection (RET) proto-oncogene in thyroid C-cells.

Human relevance of thyroid C-cell tumors in mice and rats is unknown and has not been determined by clinical studies or nonclinical studies [see Boxed Warning and Warnings and Precautions (5.1)].

Liraglutide was negative with and without metabolic activation in the Ames test for mutagenicity and in a human peripheral blood lymphocyte chromosome aberration test for clastogenicity. Liraglutide was negative in repeat-dose in vivo micronucleus tests in rats.

In rat fertility studies using subcutaneous doses of 0.1, 0.25 and 1.0 mg/kg/day liraglutide, males were treated for 4 weeks prior to and throughout mating and females were treated 2 weeks prior to and throughout mating until gestation day 17. No direct adverse effects on male fertility was observed at doses up to 1.0 mg/kg/day, a high dose yielding an estimated systemic exposure 11- times the human exposure at the MRHD, based on plasma AUC. In female rats, an increase in early embryonic deaths occurred at 1.0 mg/kg/day. Reduced body weight gain and food consumption were observed in females at the 1.0 mg/kg/day dose.

Clinical Studies

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 A1c 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 [see Dosage and Administration (2)].

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 HbA1c 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/m2.

Table 3 Results of a 52-week monotherapy triala

Victoza

1.8 mg

Victoza

1.2 mg

 
Glimepiride 8 mg

Intent-to-Treat Population (N)

246

251

 
248

HbA1c (%) (Mean)

Baseline

8.2

8.2

 
8.2

Change from baseline (adjusted mean) b

-1.1

-0.8

 
-0.5

Difference from glimepiride arm (adjusted mean) b

95% Confidence Interval

-0.6**

(-0.8, -0.4)

-0.3*

(-0.5, -0.1)

Percentage of patients achieving A1c <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

95% Confidence Interval

-20**

(-29, -12)

-10*

(-19, -1)

Body Weight (kg) (Mean)

Baseline

92.6

92.1

 
93.3

Change from baseline (adjusted mean) b

-2.5

-2.1

 
+1.1

Difference from glimepiride arm (adjusted mean) b

95% Confidence Interval

-3.6**

(-4.3, -2.9)

-3.2**

(-3.9, -2.5)

aIntent-to-treat population using last observation on study

bLeast squares mean adjusted for baseline value

*p-value <0.05

**p-value <0.0001

Figure 3 Mean HbA1c 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 HbA1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA1c 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/m2.

Table 4 Results of a 26-week trial of Victoza as add-on to metformina

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

HbA1c (%) (Mean)

Baseline

8.4

8.3

 
8.4
 
8.4

Change from baseline (adjusted mean) b

-1.0

-1.0

 
+0.1
 
-1.0

Difference from placebo + metformin arm (adjusted mean) b

95% Confidence Interval

-1.1**

(-1.3, -0.9)

-1.1**

(-1.3, -0.9)

Difference from glimepiride + metformin arm (adjusted mean) b

95% Confidence Interval

0.0

(-0.2, 0.2)

0.0

(-0.2, 0.2)

Percentage of patients achieving A1c <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

95% Confidence Interval

-38**

(-48, -27)

-37**

(-47, -26)

Difference from glimepiride + metformin arm (adjusted mean) b

95% Confidence Interval

-7

(-16, 2)

-6

(-15, 3)

Body Weight (kg) (Mean)

Baseline

88.0

88.5

 
91.0
 
89.0

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

95% Confidence Interval

-3.8**

(-4.5, -3.0)

-3.5**

(-4.3, -2.8)

aIntent-to-treat population using last observation on study

bLeast 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/m2.

The primary endpoint was the change in HbA1c from baseline to Week 26. Treatment with Victoza 1.2 mg and Victoza 1.8 mg resulted in statistically significant reductions in HbA1c 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

HbA1c (%) (Mean)

Baseline

8.4

8.4

 
8.5

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 A1c <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)

aIntent-to-treat population using last observation on study

bLeast squares mean adjusted for baseline value

**p-value <0.0001

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

Combination Therapy with Metformin and Insulin

This 26-week open-label trial enrolled 988 patients with inadequate glycemic control (HbA1c 7-10%) on metformin (≥1500 mg/day) alone or inadequate glycemic control (HbA1c 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 HbA1c <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 [see Adverse Reactions (6.1)]. The remaining 323 patients with HbA1c ≥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/m2.

Treatment with insulin detemir as add-on to Victoza 1.8 mg + metformin resulted in statistically significant reductions in HbA1c 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 HbA1c < 7% after 12 weeks of Metformin and Victozaa

Insulin detemir + Victoza + Metformin

Victoza + Metformin

Intent-to-Treat Population (N)

162

157

HbA1c (%) (Mean)

Baseline (week 0)

7.6

7.6

Change from baseline (adjusted mean)

-0.5

0

 
Difference from Victoza + metformin arm (LS mean) b

95% Confidence Interval

-0.5**

(-0.7, -0.4)

Percentage of patients achieving A1c <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

95% Confidence Interval

-31** (-39, -23)

aIntent-to-treat population using last observation on study

bLeast 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/m2.

Treatment with Victoza 1.2 mg and 1.8 mg as add-on to glimepiride resulted in a statistically significant reduction in mean HbA1c 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 sulfonylureaa

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

HbA1c (%) (Mean)

Baseline

8.5

8.5

 
8.4
 
8.4

Change from baseline (adjusted mean) b

-1.1

-1.1

 
+0.2
 
-0.4

Difference from placebo + glimepiride arm (adjusted mean) b

95% Confidence Interval

-1.4**

(-1.6, -1.1)

-1.3**

(-1.5, -1.1)

Percentage of patients achieving A1c <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

95% Confidence Interval

-47**

(-58, -35)

-46**

(-58, -35)

Body Weight (kg) (Mean)

Baseline

83.0

80.0

 
81.9
 
80.6

Change from baseline (adjusted mean) b

-0.2

+0.3

 
-0.1
 
+2.1

Difference from placebo + glimepiride arm (adjusted mean) b

95% Confidence Interval

-0.1

(-0.9, 0.6)

0.4

(-0.4, 1.2)

aIntent-to-treat population using last observation on study

bLeast 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/m2.

Treatment with Victoza as add-on to glimepiride and metformin resulted in a statistically significant mean reduction in HbA1c 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 sulfonylureaa

Victoza

1.8 mg +

Metformin +

Glimepiride

Placebo +

Metformin +

Glimepiride

Insulin glargine +

Metformin +

Glimepiride

Intent-to-Treat Population (N)

230

114

 
232

HbA1c (%) (Mean)

Baseline

8.3

8.3

 
8.1

Change from baseline (adjusted mean) b

-1.3

-0.2

 
-1.1

Difference from placebo + metformin + glimepiride arm (adjusted mean) b

95% Confidence Interval

-1.1**

(-1.3, -0.9)

Percentage of patients achieving A1c <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

95% Confidence Interval

-38**

(-46, -30)

Body Weight (kg) (Mean)

Baseline

85.8

85.4

 
85.2

Change from baseline (adjusted mean) b

-1.8

-0.4

 
1.6

Difference from placebo + metformin + glimepiride arm (adjusted mean) b

95% Confidence Interval

-1.4*

(-2.1, -0.7)

aIntent-to-treat population using last observation on study

bLeast 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/m2.

Treatment with Victoza 1.8 mg resulted in statistically significant reductions in HbA1c 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

HbA1c (%) (Mean)

Baseline

8.2

8.1

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 A1c <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)

aIntent-to-treat population using last observation carried forward

bLeast 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/m2.

Treatment with Victoza as add-on to metformin and rosiglitazone produced a statistically significant reduction in mean HbA1c 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 thiazolidinedionea

Victoza

1.8 mg +

Metformin +

Rosiglitazone

Victoza

1.2 mg +

Metformin +

Rosiglitazone

Placebo + Metformin +

 
Rosiglitazone

Intent-to-Treat Population (N)

178

177

 
175

HbA1c (%) (Mean)

Baseline

8.6

8.5

 
8.4

Change from baseline (adjusted mean) b

-1.5

-1.5

 
-0.5

Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b

95% Confidence Interval

-0.9**

(-1.1, -0.8)

-0.9**

(-1.1, -0.8)

Percentage of patients achieving A1c <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

95% Confidence Interval

-36**

(-44, -27)

-32**

(-41, -23)

Body Weight (kg) (Mean)

Baseline

94.9

95.3

 
98.5

Change from baseline (adjusted mean) b

-2.0

-1.0

 
+0.6

Difference from placebo + metformin + rosiglitazone arm (adjusted mean) b

95% Confidence Interval

-2.6**

(-3.4, -1.8)

-1.6**

(-2.4, -1.0)

aIntent-to-treat population using last observation on study

bLeast 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 m2), 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 HbA1c ≤ 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/m2. Approximately half of patients had an eGFR between 30 and <45mL/min/1.73 m2.

Treatment with Victoza resulted in a statistically significant reduction in HbA1c 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 Impairmenta

Victoza 1.8 mg + insulin and/or OAD

Placebo + insulin and/or OAD

Intent to Treat Population (N)

140

137

HbA1c (%)

Baseline (mean)

8.1

8.0

Change from baseline (estimated mean) b, c

-0.9

-0.4

Difference from placebob, c

95% Confidence Interval

-0.6*

(-0.8, -0.3)

Proportion achieving HbA1c < 7% d

39.3

19.7

FPG (mg/dL)

Baseline (mean)

171

167

Change from baseline (estimated mean) e

-22

-10

Difference from placeboe

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 HbA1c < 7%. When applying the multiple imputation method described in b) above, the estimated percents achieving HbA1c < 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

14.2 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/m2. 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 m2 and 41.8% of patients had mild renal impairment (eGFR 60 to 90 mL/min/1.73m2), 20.7% had moderate renal impairment (eGFR 30 to 60 mL/min/1.73m2) and 2.4% of patients had severe renal impairment (eGFR < 30 mL/min/1.73m2). 

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 time to first occurrence of MACE. The estimated hazard ratio (95% CI) for time to first MACE was 0.87 (0.78, 0.97). Refer to Figure 5 and Table 12.

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 (0.74, 0.97).

Figure 5 Kaplan-Meier: Time to First Occurrence of a MACE in the LEADER Trial (Patients with T2DM and Atherosclerotic CVD)

Table 12 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 infarctiond

281 (6.0%)

317 (6.8%)

0.88 (0.75;1.03)

Non-fatal stroked

159 (3.4%)

177 (3.8%)

0.89 (0.72;1.11)

Cardiovascular deathd

219 (4.7%)

278 (6%)

0.78 (0.66;0.93)

aFull analysis set (all randomized patients)

bCox-proportional hazards model with treatment as a factor

cp-value for superiority (2-sided) 0.011

dNumber and percentage of first events

How Supplied/Storage and Handling

How Supplied

Victoza is available in the following package sizes containing disposable, pre-filled, multi-dose pens. Each individual pen delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL).

2 x Victoza pen NDC 0169-4060-12

3 x Victoza pen NDC 0169-4060-13

Each Victoza pen is for use by a single patient. A Victoza pen must never be shared between patients, even if the needle is changed.

Recommended Storage

Prior to first use, Victoza should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC) (Table 13). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze Victoza and do not use Victoza if it has been frozen.

After initial use of the Victoza pen, the pen can be stored for 30 days at controlled room temperature (59°F to 86°F; 15°C to 30°C) or in a refrigerator (36°F to 46°F; 2°C to 8°C). Keep the pen cap on when not in use. Victoza should be protected from excessive heat and sunlight. Always remove and safely discard the needle after each injection and store the Victoza pen without an injection needle attached. This will reduce the potential for contamination, infection, and leakage while also ensuring dosing accuracy. Always use a new needle for each injection to prevent contamination.

Table 13 Recommended Storage Conditions for the Victoza Pen

Prior to first use

After first use

Refrigerated

36°F to 46°F (2°C to 8°C)

Room Temperature

59°F to 86°F (15°C to 30°C)

Refrigerated

36°F to 46°F (2°C to 8°C)

Until expiration date

30 days

Patient Counseling Information

FDA-Approved Medication Guide

See separate leaflet.

Risk of Thyroid C-cell Tumors

Inform patients that liraglutide causes benign and malignant thyroid C-cell tumors in mice and rats and that the human relevance of this finding has not been determined. Counsel patients to report symptoms of thyroid tumors (e.g., a lump in the neck, hoarseness, dysphagia, or dyspnea) to their physician [see Boxed Warning and Warnings and Precautions (5.1)].

Dehydration and Renal Failure

Advise patients treated with Victoza of the potential risk of dehydration due to gastrointestinal adverse reactions and to take precautions to avoid fluid depletion. Inform patients of the potential risk for worsening renal function, which in some cases may require dialysis.

Pancreatitis

Inform patients of the potential risk for pancreatitis. Explain that persistent severe abdominal pain that may radiate to the back and which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue Victoza promptly and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].

Acute Gallbladder Disease

Inform patients of the potential risk for cholelithiasis or cholecystitis. Instruct patients to contact their physician if cholelithiasis or cholecystitis is suspected for appropriate clinical follow-up.

Never Share a Victoza Pen Between Patients

Advise patients that they must never share a Victoza pen with another person, even if the needle is changed, because doing so carries a risk for transmission of blood-borne pathogens.

Hypersensitivity Reactions

Inform patients that serious hypersensitivity reactions have been reported during postmarketing use of Victoza. Advise patients on the symptoms of hypersensitivity reactions and instruct them to stop taking Victoza and seek medical advice promptly if such symptoms occur [see Warnings and Precautions (5.6)].

Jaundice and Hepatitis

Inform patients that jaundice and hepatitis have been reported during postmarketing use of liraglutide. Instruct patients to contact their physician if they develop jaundice.

Instructions

Advise patients that the most common side effects of Victoza are headache, nausea and diarrhea. Nausea is most common when first starting Victoza, but decreases over time in the majority of patients and does not typically require discontinuation of Victoza.

Inform patients not to take an extra dose of Victoza to make up for a missed dose. If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. If more than 3 days have elapsed since the last dose, advise the patient to reinitiate Victoza at 0.6 mg to mitigate any gastrointestinal symptoms associated with reinitiation of treatment. Victoza should be titrated at the discretion of the prescribing physician [see Dosage and Administration (2)].

Date of Issue: August 25, 2017

Version: 10

Victoza® is a registered trademark of Novo Nordisk A/S.

PATENT Information: http://novonordisk-us.com/patients/products/product-patents.html

© 2010-2017 Novo Nordisk

Manufactured by:

Novo Nordisk A/S

DK-2880 Bagsvaerd, Denmark

For information about Victoza contact:

Novo Nordisk Inc.

800 Scudders Mill Road

Plainsboro, NJ 08536

1-877-484-2869

Medication Guide

Victoza® (VIC-tow-za)
(liraglutide) injection, for subcutaneous use

Read this Medication Guide before you start using Victoza and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

What is the most important information I should know about Victoza?
Victoza may cause serious side effects, including:

Possible thyroid tumors, including cancer. Tell your healthcare provider if you get a lump or swelling in your neck, hoarseness, trouble swallowing, or shortness of breath. These may be symptoms of thyroid cancer. In studies with rats and mice, Victoza and medicines that work like Victoza caused thyroid tumors, including thyroid cancer. It is not known if Victoza will cause thyroid tumors or a type of thyroid cancer called medullary thyroid carcinoma (MTC) in people.
Do not use Victoza if you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC), or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).

What is Victoza?

Victoza is an injectable prescription medicine for adults with type 2 diabetes mellitus that:

along with diet and exercise may improve blood sugar (glucose).
along with your current treatment for your cardiovascular disease may reduce the risk of major cardiovascular events such as heart attack, stroke or death.

Victoza is not a substitute for insulin and is not for use in people with type 1 diabetes or people with diabetic ketoacidosis.

It is not known if Victoza can be used with mealtime insulin.

It is not known if Victoza is safe and effective for use in children.

Who should not use Victoza?
Do not use Victoza if:

you or any of your family have ever had a type of thyroid cancer called medullary thyroid carcinoma (MTC) or if you have an endocrine system condition called Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
you are allergic to liraglutide or any of the ingredients in Victoza. See the end of this Medication Guide for a complete list of ingredients in Victoza.

What should I tell my healthcare provider before using Victoza?
Before using Victoza, tell your healthcare provider if you have any other medical conditions, including if you:

have or have had problems with your pancreas, kidneys, or liver.
have severe problems with your stomach, such as slowed emptying of your stomach (gastroparesis) or problems with digesting food.
are pregnant or plan to become pregnant. It is not known if Victoza will harm your unborn baby. Tell your healthcare provider if you become pregnant while using Victoza.
are breastfeeding or plan to breastfeed. It is not known if Victoza passes into your breast milk. You should talk with your healthcare provider about the best way to feed your baby while using Victoza.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Victoza may affect the way some medicines work and some medicines may affect the way Victoza works.

Before using Victoza, talk to your healthcare provider about low blood sugar and how to manage it. Tell your healthcare provider if you are taking other medicines to treat diabetes, including insulin or sulfonylureas.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.

How should I use Victoza?

Read the Instructions for Use that comes with Victoza.
Use Victoza exactly as your healthcare provider tells you to.
Your healthcare provider should show you how to use Victoza before you use it for the first time.
Victoza is injected under the skin (subcutaneously) of your stomach (abdomen), thigh, or upper arm. Do not inject Victoza into a muscle (intramuscularly) or vein (intravenously).
Use Victoza 1 time each day, at any time of the day.
If you miss a dose of Victoza, take the missed dose at the next scheduled dose. Do not take 2 doses of Victoza at the same time.
Victoza may be taken with or without food.
Do not mix insulin and Victoza together in the same injection.
You may give an injection of Victoza and insulin in the same body area (such as your stomach area), but not right next to each other.
Change (rotate) your injection site with each injection. Do not use the same site for each injection.
Do not share your Victoza pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.

Your dose of Victoza and other diabetes medicines may need to change because of:

change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.

What are the possible side effects of Victoza?
Victoza may cause serious side effects, including:

See “What is the most important information I should know about Victoza?”
inflammation of your pancreas(pancreatitis). Stop using Victoza and call your healthcare provider right away if you have severe pain in your stomach area (abdomen) that will not go away, with or without vomiting. You may feel the pain from your abdomen to your back.
low blood sugar (hypoglycemia). Your risk for getting low blood sugar may be higher if you use Victoza with another medicine that can cause low blood sugar, such as a sulfonylurea or insulin. Signs and symptoms of low blood sugar may include:
dizziness or light-headedness
sweating
confusion or drowsiness
headache
blurred vision
slurred speech
shakiness
fast heartbeat
anxiety, irritability, or mood changes
hunger
weakness
feeling jittery
kidney problems (kidney failure). In people who have kidney problems, diarrhea, nausea, and vomiting may cause a loss of fluids (dehydration) which may cause kidney problems to get worse.
seriousallergic reactions. Stop using Victoza and get medical help right away, if you have any symptoms of a serious allergic reaction including:
Swelling of your face, lips, tongue or throat
Problems breathing or swallowing
Severe rash or itching
Fainting or feeling dizzy
Very rapid heartbeat
gallbladder problems. Gallbladder problems have happened in some people who take Victoza. Tell your healthcare provider right away if you get symptoms of gallbladder problems which may include:
pain in the right or middle upper stomach area
nausea and vomiting
fever
your skin or the white part of your eyes turns yellow

The most common side effects of Victoza may include: nausea, diarrhea, vomiting, decreased appetite, indigestion and constipation.

Talk to your healthcare provider about any side effect that bothers you or does not go away. These are not all the possible side effects of Victoza.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1‑800‑FDA‑1088.

General information about the safe and effective use of Victoza.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Victoza for a condition for which it was not prescribed. Do not give Victoza to other people, even if they have the same symptoms that you have. It may harm them. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Victoza that is written for health professionals.

What are the ingredients in Victoza?
Active Ingredient:
liraglutide
Inactive Ingredients:
disodium phosphate dihydrate, propylene glycol, phenol and water for injection

This Medication Guide has been approved by the U.S. Food and Drug Administration.

Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark

Victoza® is a registered trademark of Novo Nordisk A/S.

For more information, go to Victoza.com or call 1-877-484-2869.

PATENT Information: http://novonordisk-us.com/patients/products/product-patents.html

© 2010-2017 Novo Nordisk
Revised: August 2017

INSTRUCTIONS FOR USE

Victoza (liraglutide [rDNA origin]) injection

First read the Medication Guide that comes with your Victoza pen and then read these Patient Instructions for Use for information about how to use your Victoza pen the right way.

These instructions do not take the place of talking with your healthcare provider about your medical condition or your treatment.

Do not share your Victoza Pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.

Your Victoza pen contains 3 mL of Victoza and will deliver doses of 0.6 mg, 1.2 mg or 1.8 mg. The number of doses that you can take with a Victoza pen depends on the dose of medicine that is prescribed for you. Your healthcare provider will tell you how much Victoza to take.

Victoza pen should be used with Novo Nordisk disposable needles. Talk to your healthcare provider or pharmacist for more information about needles for your Victoza pen.

Important Information

Do not share your Victoza pen with other people, even if the needle has been changed. You may give other people a serious infection, or get a serious infection from them.
Always use a new needle for each injection. Do not reuse or share your needles with other people. You may give other people a serious infection, or get a serious infection from them.
Keep your Victoza pen and all medicines out of the reach of children.
If you drop your Victoza pen, repeat “First Time Use For Each New Pen” (steps A through D).
Be careful not to bend or damage the needle.
Do not use the cartridge scale to measure how much Victoza to inject.
Be careful when handling used needles to avoid needle stick injuries.
You can use your Victoza pen for up to 30 days after you use it the first time.

First Time Use for Each New Pen

Step A. Check the Pen

Take your new Victoza pen out of the refrigerator.
Wash hands with soap and water before use.
Check pen label before each use to make sure it is your Victoza pen.
Pull off pen cap.
Check Victoza in the cartridge. The liquid should be clear, colorless and free of particles. If not, do not use.
Wipe the rubber stopper with an alcohol swab.

Step B. Attach the Needle

Remove protective tab from outer needle cap.
Push outer needle cap containing the needle straight onto the pen, then screw needle on until secure.
Pull off outer needle cap. Do not throw away.
Pull off inner needle cap and throw away. A small drop of liquid may appear. This is normal.

Step C. Dial to the Flow Check Symbol

This step is done only ONCE for each new pen and is ONLY required the first time you use a new pen.

Turn dose selector until flow check symbol (--) lines up with pointer. The flow check symbol does not administer the dose as prescribed by your healthcare provider.
To select the dose prescribed by your healthcare provider, continue to Step G under “Routine Use”.

Step D. Prepare the Pen

Hold pen with needle pointing up.
Tap cartridge gently with your finger a few times to bring any air bubbles to the top of the cartridge.
Keep needle pointing up and press dose button until 0 mg lines up with pointer. Repeat steps C and D, up to 6 times, until a drop of Victoza appears at the needle tip.

If you still see no drop of Victoza, use a new pen and contact Novo Nordisk at 1-877-484-2869.

Continue to Step G under "Routine Use" →

Routine Use

Step E. Check the Pen

Take your Victoza pen from where it is stored.
Wash hands with soap and water before use.
Check pen label before each use to make sure it is your Victoza pen.
Pull off pen cap.
Check Victoza in the cartridge. The liquid should be clear, colorless and free of particles. If not, do not use.
Wipe the rubber stopper with an alcohol swab.

Step F. Attach the Needle

Remove protective tab from outer needle cap.
Push outer needle cap containing the needle straight onto the pen, then screw needle on until secure.
Pull off outer needle cap. Do not throw away.
Pull off inner needle cap and throw away. A small drop of liquid may appear. This is normal.

Step G. Dial the Dose

Victoza pen can give a dose of 0.6 mg (starting dose), 1.2 mg or 1.8 mg. Be sure that you know the dose of Victoza that is prescribed for you.
Turn the dose selector until your needed dose lines up with the pointer (0.6 mg, 1.2 mg or 1.8 mg).
You will hear a "click" every time you turn the dose selector. Do not set the dose by counting the number of clicks you hear.
If you select a wrong dose, change it by turning the dose selector backwards or forwards until the correct dose lines up with the pointer. Be careful not to press the dose button when turning the dose selector. This may cause Victoza to come out.

Step H. Injecting the Dose

Insert needle into your skin in the stomach, thigh or upper arm. Use the injection technique shown to you by your healthcare provider. Do not inject Victoza into a vein or muscle.
Press down on the center of the dose button to inject until 0 mg lines up with the pointer.
Be careful not to touch the dose display with your other fingers. This may block the injection.
Keep the dose button pressed down and make sure that you keep the needle under the skin for a full count of 6 seconds to make sure the full dose is injected. Keep your thumb on the injection button until you remove the needle from your skin.
Change (rotate) your injection sites within the area you choose for each dose. Do not use the same injection site for each injection.

Step I. Withdraw Needle

You may see a drop of Victoza at the needle tip. This is normal and it does not affect the dose you just received. If blood appears after you take the needle out of your skin, apply light pressure, but do not rub the area.

Step J. Remove and Dispose of the Needle

Carefully put the outer needle cap over the needle. Unscrew the needle.
Safely remove the needle from your Victoza pen after each use.
Put your used Victoza pen and needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and pens in your household trash.
If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
made of a heavy-duty plastic
can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out
upright and stable during use
leak-resistant
properly labeled to warn of hazardous waste inside the container
When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. Do not reuse or share your needles with other people. For more information about the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA’s website at: http://www.fda.gov/safesharpsdisposal.
Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.

Caring for your Victoza pen

After removing the needle, put the pen cap on your Victoza pen and store your Victoza pen without the needle attached.
Do not try to refill your Victoza pen - it is prefilled and is disposable.
Do not try to repair your pen or pull it apart.
Keep your Victoza pen away from dust, dirt and liquids.
If cleaning is needed, wipe the outside of the pen with a clean, damp cloth.

How should I store Victoza?

Before use:

Store your new, unused Victoza pen in the refrigerator at 36ºF to 46ºF (2ºC to 8ºC).
If Victoza is stored outside of refrigeration (by mistake) prior to first use, it should be used or thrown away within 30 days.
Do not freeze Victoza or use Victoza if it has been frozen. Do not store Victoza near the refrigerator cooling element.

Pen in use:

Store your Victoza pen for 30 days at 59ºF to 86ºF (15ºC to 30ºC), or in a refrigerator at 36ºF to 46ºF (2°C to 8°C).
When carrying the pen away from home, store the pen at a temperature between 59ºF to 86ºF (15ºC to 30ºC).
If Victoza has been exposed to temperatures above 86ºF (30°C), it should be thrown away.
Protect your Victoza pen from heat and sunlight.
Keep the pen cap on when your Victoza pen is not in use.
Use a Victoza pen for only 30 days. Throw away a used Victoza pen after 30 days, even if some medicine is left in the pen.

Principal Display Panel - 3 Victoza Pens

NDC 0169-4060-13

List 406013

Victoza®

liraglutide

(rDNA origin) injection

18 mg/3 mL (6 mg/mL)

Each pen delivers doses of 0.6 mg, 1.2 mg or 1.8 mg

Subcutaneous use only

Discard pen 30 days after first use

REFRIGERATE - DO NOT FREEZE

SINGLE PATIENT USE ONLY

Rx Only

Contains: 3 Victoza Pens, Product Literature

Dispense the enclosed Medication Guide to each patient

Intended for use with Novo Nordisk disposable needles

3 pens

Principal Display Panel - 2 Victoza Pens

NDC 0169-4060-12

List 406012

Victoza®

liraglutide

(rDNA origin) injection

18 mg/3 mL (6 mg/mL)

Each pen delivers doses of 0.6 mg, 1.2 mg or 1.8 mg

Subcutaneous use only

Discard pen 30 days after first use

REFRIGERATE - DO NOT FREEZE

SINGLE PATIENT USE ONLY

Rx Only

Contains: 2 Victoza Pens, Product Literature

Dispense the enclosed Medication Guide to each patient

Intended for use with Novo Nordisk disposable needles

2 pens

Victoza 
liraglutide injection
Product Information
Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:0169-4060
Route of Administration SUBCUTANEOUS DEA Schedule     
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LIRAGLUTIDE (LIRAGLUTIDE) LIRAGLUTIDE 6 mg  in 1 mL
Inactive Ingredients
Ingredient Name Strength
SODIUM PHOSPHATE, DIBASIC, DIHYDRATE 1.42 mg  in 1 mL
PHENOL 5.5 mg  in 1 mL
PROPYLENE GLYCOL 14 mg  in 1 mL
WATER  
Packaging
# Item Code Package Description
1 NDC:0169-4060-13 3 SYRINGE, PLASTIC in 1 CARTON
1 3 mL in 1 SYRINGE, PLASTIC
2 NDC:0169-4060-12 2 SYRINGE, PLASTIC in 1 CARTON
2 3 mL in 1 SYRINGE, PLASTIC
3 NDC:0169-4060-90 1 SYRINGE, PLASTIC in 1 CARTON
3 3 mL in 1 SYRINGE, PLASTIC
4 NDC:0169-4060-97 1 SYRINGE, PLASTIC in 1 CARTON
4 3 mL in 1 SYRINGE, PLASTIC
5 NDC:0169-4060-98 1 SYRINGE, PLASTIC in 1 CARTON
5 3 mL in 1 SYRINGE, PLASTIC
6 NDC:0169-4060-99 1 SYRINGE, PLASTIC in 1 CARTON
6 3 mL in 1 SYRINGE, PLASTIC
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
NDA NDA022341 01/25/2010
Labeler - Novo Nordisk (622920320)
Establishment
Name Address ID/FEI Operations
Novo Nordisk A/S 305914798 MANUFACTURE(0169-4060)
Establishment
Name Address ID/FEI Operations
Novo Nordisk Pharmaceuticals Industries, Inc. 622920320 MANUFACTURE(0169-4060)
Establishment
Name Address ID/FEI Operations
Novo Nordisk A/S 305156788 API MANUFACTURE(0169-4060)
Revised: 08/2017
 
Novo Nordisk
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