—新型降糖药Victoza(liraglutide)中文药名：利拉鲁肽注射剂在欧美上市
美国食品药品管理局（FDA）近日批准Victoza(liraglutide，利拉鲁肽)注射剂用于部分成年患者2型糖尿病的治疗。Victoza属胰高血糖素样肽1(GLP-1)类似物药物（注射剂，每日注射一次），能够在患者进食后促使其胰腺分泌更多胰岛素，对于没有进行适当的饮食控制和运动的患者，Victoza不被推荐单独用于糖尿病的初期治疗。
FDA药品审评与研究中心新陈代谢与内分泌室主任、医学博士Mary Parks说，“糖尿病是引起死亡和致残的一个主要原因，每年新诊断出的糖尿病患者超过了1500万人。对于预防或控制长期的糖尿病并发症来看，控制血糖水平是非常重要的，Victoza为部分2型糖尿病患者提供了控制血糖水平的备选方案。”
Victoza最常见的不良反应包括头痛、恶心和腹泻。其他不良反应包括荨麻疹等过敏样反应。有3900位患者参加的5个临床试验结果显示，使用Victoza的患者发生胰腺炎（胰腺的一种炎症）的可能性要大于使用其他治疗药物的患者。当患者出现严重腹痛，伴随或未伴随恶心、呕吐时，应停止使用Victoza，当确诊为胰腺炎后，不应再次使用Victoza进行治疗。有胰腺炎病史的患者应慎用。动物试验显示，Victoza会引起大鼠和小鼠出现甲状腺瘤。因此，尚不能确认是否会引起人甲状腺瘤或癌，为此，在继续进行研究以证明可以扩大使用之前，Victoza不能作为治疗2型糖尿病的一线药物，也不能用于治疗已患甲状腺髓样癌的患者。

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Victoza safely and effectively. See full prescribing information for Victoza.
Victoza ® (liraglutide [rDNA origin] injection), solution for subcutaneous use
Initial U.S. Approval: 2010
WARNING: RISK OF THYROID C-CELL TUMORSSee full prescribing information for complete boxed warning.
• Liraglutide causes thyroid C-cell tumors at clinically relevant exposures in both genders of rats and mice. It is unknown whether 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 ( 5.1 , 13.1).
• Victoza is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk of MTC and the symptoms of thyroid tumors (4, 5.1).
RECENT MAJOR CHANGES
Boxed Warning 03/2015
Indications and Usage: Important Limitations of Use (1.1) 03/2015
Warnings and Precautions: Risk of Thyroid C-cell Tumors (5.1) 03/2015
Warnings and Precautions:
Never Share a Victoza Pen Between Patients (5.3) 02/2015
INDICATIONS AND USAGE
Victoza is a glucagon-like peptide-1 (GLP-1) receptor agonist indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (1).
Important Limitations of Use (1.1):
• Not recommended as first-line therapy for patients inadequately controlled on diet and exercise (5.1).
• Has not been studied in patients with a history of pancreatitis. Consider other antidiabetic therapies in patients with a history of pancreatitis (5.2).
• Not for treatment of type 1 diabetes mellitus or diabetic ketoacidosis.
• Has not been studied in combination with prandial insulin.
DOSAGE AND ADMINISTRATION
• Administer once daily at any time of day, independently of meals (2).
• Inject subcutaneously in the abdomen, thigh or upper arm (2).
• The injection site and timing can be changed without dose adjustment (2).
• Initiate at 0.6 mg per day for one week. This dose is intended to reduce gastrointestinal symptoms during initial titration, and is not effective for glycemic control. After one week, increase the dose 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 (2).
DOSAGE FORMS AND STRENGTHS
• Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL) (3).
CONTRAINDICATIONS
Victoza is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2 (4).
Victoza is contraindicated in patients with a prior serious hypersensitivity reaction to Victoza or any of the product components (4).
WARNINGS AND PRECAUTIONS
• Thyroid C-cell Tumors: See Boxed Warning (5.1).
• Pancreatitis: Postmarketing reports, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis. Discontinue promptly if pancreatitis is suspected. Do not restart if pancreatitis is confirmed. Consider other antidiabetic therapies in patients with a history of pancreatitis (5.2).
• Never share a Victoza pen between patients, even if the needle is changed (5.3).
• Serious Hypoglycemia: Can occur when Victoza is used with an insulin secretagogue (e.g. a sulfonylurea) or insulin. Consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia (5.4).
• Renal Impairment: Has been reported postmarketing, usually in association with nausea, vomiting, diarrhea, or dehydration which may sometimes require hemodialysis. Use caution when initiating or escalating doses of Victoza in patients with renal impairment (5.5).
• Hypersensitivity: Postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema). The patient should discontinue Victoza and other suspect medications and promptly seek medical advice (5.6).
• Macrovascular Outcomes: There have been no studies establishing conclusive evidence of macrovascular risk reduction with Victoza or any other antidiabetic drug (5.7).
ADVERSE REACTIONS
• The most common adverse reactions, reported in ≥5% of patients treated with Victoza and more commonly than in patients treated with placebo, are: headache, nausea, diarrhea and anti-liraglutide antibody formation (6).
• Immunogenicity-related events, including urticaria, were more common among Victoza-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials (6).
To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
• Victoza delays gastric emptying. May impact absorption of concomitantly administered oral medications. Use caution (7).
USE IN SPECIFIC POPULATIONS
• Limited data in patients with renal or hepatic impairment. (8.6, 8.7).
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 3/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
Victoza is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
1.1 Important Limitations of Use
Victoza is not recommended as first-line therapy for patients who have inadequate glycemic control on diet and exercise because of the uncertain relevance of the rodent C-cell tumor findings to humans. Prescribe Victoza only to patients for whom the potential benefits are considered to outweigh the potential risk [see Warnings and Precautions (5.1)].
• Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis has been observed in patients treated with Victoza. Victoza has not been studied in patients with a history of pancreatitis. It is unknown whether patients with a history of pancreatitis are at increased risk for pancreatitis while using Victoza. Other antidiabetic therapies should be considered in patients with a history of pancreatitis.
• 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.
2 DOSAGE AND ADMINISTRATION
Victoza can be administered once daily at any time of day, independently of meals, and can be injected subcutaneously in the abdomen, thigh or upper arm. The injection site and timing can be changed without dose adjustment.
For all patients, Victoza should be initiated 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.
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)].
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.
Victoza solution should be inspected prior to each injection, and the solution should be used only if it is clear, colorless, and contains no particles.
If a dose is missed, the once-daily regimen should be resumed as prescribed with the next scheduled dose. An extra dose or increase in dose should not be taken to make-up for the missed dose.
Based on the elimination half-life, patients should be advised to reinitiate Victoza at 0.6 mg if more than 3 days have elapsed since the last Victoza dose. This approach will mitigate any gastrointestinal symptoms associated with reinitiation of treatment. Upon reinitiation, Victoza should be titrated at the discretion of the prescribing healthcare provider.
3 DOSAGE FORMS AND STRENGTHS
Solution for subcutaneous injection, pre-filled, multi-dose pen that delivers doses of 0.6 mg, 1.2 mg, or 1.8 mg (6 mg/mL, 3 mL).
4 CONTRAINDICATIONS
Victoza is contraindicated in patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2).
Victoza is contraindicated in patients with a prior serious hypersensitivity reaction to Victoza or to any of the product components.
5 WARNINGS AND PRECAUTIONS
5.1 Risk of Thyroid C-cell Tumors
Liraglutide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors (adenomas and/or carcinomas) at clinically relevant exposures in both genders of rats and mice [see Nonclinical Toxicology (13.1)]. Malignant thyroid C-cell carcinomas were detected in rats and mice. It is unknown whether Victoza will cause thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans, as the human relevance of liraglutide-induced rodent thyroid C-cell tumors has not been determined.
Cases of MTC in patients treated with Victoza have been reported in the postmarketing period; the data in these reports are insufficient to establish or exclude a causal relationship between MTC and Victoza use in humans.
Victoza is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2. Counsel patients regarding the potential risk for MTC with the use of Victoza and inform them of symptoms of thyroid tumors (e.g. a mass in the neck, dysphagia, dyspnea, persistent hoarseness).
Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Victoza. Such monitoring may increase the risk of unnecessary procedures, due to low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.
5.2 Pancreatitis
Based on spontaneous postmarketing reports, acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with Victoza. After initiation of Victoza, observe patients carefully for signs and symptoms of pancreatitis (including persistent severe abdominal pain, sometimes radiating to the back and which may or may not be accompanied by vomiting). If pancreatitis is suspected, Victoza should promptly be discontinued and appropriate management should be initiated. If pancreatitis is confirmed, Victoza should not be restarted. Consider antidiabetic therapies other than Victoza in patients with a history of pancreatitis.
In clinical 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.
5.3 Never Share a Victoza Pen Between Patients
Victoza pens must never be shared between patients, even if the needle is changed. Pen-sharing poses a risk for transmission of blood-borne pathogens.
5.4 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 Adverse Reactions (6.1)].
5.5 Renal Impairment
Victoza has not been found to be directly nephrotoxic in animal studies or clinical trials. There have been postmarketing reports of acute renal failure and worsening of chronic renal failure, which may sometimes require hemodialysis in Victoza-treated patients [see Adverse Reactions (6.2)]. Some of these events were reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration [see Adverse Reactions (6.1)]. Some of the reported events occurred in patients receiving one or more medications known to affect renal function or hydration status. Altered renal function has been reversed in many of the reported cases with supportive treatment and discontinuation of potentially causative agents, including Victoza. Use caution when initiating or escalating doses of Victoza in patients with renal impairment [see Use in Specific Populations (8.6)].
5.6 Hypersensitivity Reactions
There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylactic reactions and angioedema) in patients treated with Victoza. If a hypersensitivity reaction occurs, the patient should discontinue Victoza and other suspect medications and promptly seek medical advice.
Angioedema has also been reported with other GLP-1 receptor agonists. Use caution in a patient with a history of angioedema with another GLP-1 receptor agonist because it is unknown whether such patients will be predisposed to angioedema with Victoza.
5.7 Macrovascular Outcomes
There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with Victoza or any other antidiabetic drug.
6 ADVERSE REACTIONS
The following serious adverse reactions are described below or elsewhere in the prescribing information:
• Risk of Thyroid C-cell Tumors [see Warnings and Precautions (5.1)]
• 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) ]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of Victoza has been evaluated in 8 clinical trials [see Clinical Studies (14)]:
• A double-blind 52-week monotherapy trial compared Victoza 1.2 mg daily, Victoza 1.8 mg daily, and glimepiride 8 mg daily.
• A double-blind 26 week add-on to metformin trial compared Victoza 0.6 mg once-daily, Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and glimepiride 4 mg once-daily.
• A double-blind 26 week add-on to glimepiride trial compared Victoza 0.6 mg daily, Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, placebo, and rosiglitazone 4 mg once-daily.
• A 26 week add-on to metformin + glimepiride trial, compared double-blind Victoza 1.8 mg once-daily, double-blind placebo, and open-label insulin glargine once-daily.
• A double-blind 26-week add-on to metformin + rosiglitazone trial compared Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily and placebo.
• An open-label 26-week add-on to metformin and/or sulfonylurea trial compared Victoza 1.8 mg once-daily and exenatide 10 mcg twice-daily.
• An open-label 26-week add-on to metformin trial compared Victoza 1.2 mg once-daily, Victoza 1.8 mg once-daily, and sitagliptin 100 mg once-daily.
• An open-label 26-week trial compared insulin detemir as add-on to Victoza 1.8 mg + metformin to continued treatment with Victoza + metformin alone.
Withdrawals
The incidence of withdrawal due to adverse events was 7.8% for Victoza-treated patients and 3.4% for comparator-treated patients in the five double-blind controlled trials of 26 weeks duration or longer. This difference was driven by withdrawals due to gastrointestinal adverse reactions, which occurred in 5.0% of Victoza-treated patients and 0.5% of comparator-treated patients. In these five trials, the most common adverse reactions leading to withdrawal for Victoza-treated patients were nausea (2.8% versus 0% for comparator) and vomiting (1.5% versus 0.1% for comparator). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2-3 months of the trials.
Common adverse reactions
Tables 1, 2, 3 and 4 summarize common adverse reactions (hypoglycemia is discussed separately) reported in seven of the eight controlled trials of 26 weeks duration or longer. Most of these adverse reactions were gastrointestinal in nature.
In the five double-blind clinical trials of 26 weeks duration or longer, gastrointestinal adverse reactions were reported in 41% of Victoza-treated patients and were dose-related. Gastrointestinal adverse reactions occurred in 17% of comparator-treated patients. Common adverse reactions that occurred at a higher incidence among Victoza-treated patients included nausea, vomiting, diarrhea, dyspepsia and constipation.
In the five double-blind and three open-label clinical trials of 26 weeks duration or longer, the percentage of patients who reported nausea declined over time. In the five double-blind trials approximately 13% of Victoza-treated patients and 2% of comparator-treated patients reported nausea during the first 2 weeks of treatment.
In the 26-week open-label trial comparing Victoza to exenatide, both in combination with metformin and/or sulfonylurea, gastrointestinal adverse reactions were reported at a similar incidence in the Victoza and exenatide treatment groups (Table 3).
In the 26-week open-label trial comparing Victoza 1.2 mg, Victoza 1.8 mg and sitagliptin 100 mg, all in combination with metformin, gastrointestinal adverse reactions were reported at a higher incidence with Victoza than sitagliptin (Table 4).
In the remaining 26-week trial, all patients received Victoza 1.8 mg + metformin during a 12-week run-in period. During the run-in period, 167 patients (17% of enrolled total) withdrew from the trial: 76 (46% of withdrawals) of these patients doing so because of gastrointestinal adverse reactions and 15 (9% of withdrawals) doing so due to other adverse events. Only those patients who completed the run-in period with inadequate glycemic control were randomized to 26 weeks of add-on therapy with insulin detemir or continued, unchanged treatment with Victoza 1.8 mg + metformin. During this randomized 26-week period, diarrhea was the only adverse reaction reported in ≥5% of patients treated with Victoza 1.8 mg + metformin + insulin detemir (11.7%) and greater than in patients treated with Victoza 1.8 mg and metformin alone (6.9%).
Table 1 Adverse reactions reported in ≥5% of Victoza-treated patients in a 52-week monotherapy trial 

All Victoza N = 497	Glimepiride N = 248
Adverse Reaction	(%)	(%)
Nausea	28.4	8.5
Diarrhea	17.1	8.9
Vomiting	10.9	3.6
Constipation	9.9	4.8
Headache	9.1	9.3

Table 2 Adverse reactions reported in ≥5% of Victoza-treated patients and occurring more frequently with Victoza compared to placebo: 26-week combination therapy trials

Add-on to Metformin Trial
	All Victoza + Metformin N = 724	Placebo + Metformin N = 121	Glimepiride + Metformin N = 242
Adverse Reaction	(%)	(%)	(%)
Nausea	15.2	4.1	3.3
Diarrhea	10.9	4.1	3.7
Headache	9.0	6.6	9.5
Vomiting	6.5	0.8	0.4
Add-on to Glimepiride Trial
	All Victoza + Glimepiride N = 695	Placebo + Glimepiride N = 114	Rosiglitazone + Glimepiride N = 231
Adverse Reaction	(%)	(%)	(%)
Nausea	7.5	1.8	2.6
Diarrhea	7.2	1.8	2.2
Constipation	5.3	0.9	1.7
Dyspepsia	5.2	0.9	2.6
Add-on to Metformin + Glimepiride
	Victoza 1.8 + Metformin + Glimepiride N = 230	Placebo + Metformin + Glimepiride N = 114	Glargine + Metformin + Glimepiride N = 232
Adverse Reaction	(%)	(%)	(%)
Nausea	13.9	3.5	1.3
Diarrhea	10.0	5.3	1.3
Headache	9.6	7.9	5.6
Dyspepsia	6.5	0.9	1.7
Vomiting	6.5	3.5	0.4
Add-on to Metformin + Rosiglitazone
	All Victoza + Metformin + Rosiglitazone N = 355	Placebo + Metformin + Rosiglitazone N = 175
Adverse Reaction	(%)	(%)
Nausea	34.6	8.6
Diarrhea	14.1	6.3
Vomiting	12.4	2.9
Headache	8.2	4.6
Constipation	5.1	1.1

Table 3 Adverse Reactions reported in ≥5% of Victoza-treated patients in a 26-Week Open-Label Trial versus Exenatide

Victoza 1.8 mg once daily + metformin and/or sulfonylurea N = 235	Exenatide 10 mcg twice daily + metformin and/or sulfonylurea N = 232
Adverse Reaction	(%)	(%)
Nausea	25.5	28.0
Diarrhea	12.3	12.1
Headache	8.9	10.3
Dyspepsia	8.9	4.7
Vomiting	6.0	9.9
Constipation	5.1	2.6

Table 4 Adverse Reactions in ≥5% of Victoza-treated patients in a 26-Week Open-Label Trial versus Sitagliptin

All Victoza + metformin N = 439	Sitagliptin 100 mg/day + metformin N = 219
Adverse Reaction	(%)	(%)
Nausea	23.9	4.6
Headache	10.3	10.0
Diarrhea	9.3	4.6
Vomiting	8.7	4.1

Immunogenicity
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients treated with Victoza may develop anti-liraglutide antibodies. Approximately 50-70% of Victoza-treated patients in the 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. Sampling was not performed uniformly across all patients in the clinical trials, and this may have resulted in an underestimate of the actual percentage of patients who developed antibodies. 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.
Among Victoza-treated patients who developed anti-liraglutide antibodies, the most common category of adverse events was that of infections, which occurred among 40% of these patients compared to 36%, 34% and 35% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. The specific infections which occurred with greater frequency among Victoza-treated antibody-positive patients were primarily nonserious upper respiratory tract infections, which occurred among 11% of Victoza-treated antibody-positive patients; and among 7%, 7% and 5% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. Among Victoza-treated antibody-negative patients, the most common category of adverse events was that of gastrointestinal events, which occurred in 43%, 18% and 19% of antibody-negative Victoza-treated, placebo-treated and active-control-treated patients, respectively. 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 the five double-blind clinical 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.
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 clinical trials of at least 26 weeks duration. Less than 0.2% of Victoza-treated patients discontinued due to injection site reactions.
Papillary thyroid carcinoma
In clinical 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.
Hypoglycemia
In the eight clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 11 Victoza-treated patients (2.3 cases per 1000 patient-years) and in two exenatide-treated patients. Of these 11 Victoza-treated patients, six patients were concomitantly using metformin and a sulfonylurea, one was concomitantly using a sulfonylurea, two were concomitantly using metformin (blood glucose values were 65 and 94 mg/dL) and two were using Victoza as monotherapy (one of these patients was undergoing an intravenous glucose tolerance test and the other was receiving insulin as treatment during a hospital stay). For these two patients on Victoza monotherapy, the insulin treatment was the likely explanation for the hypoglycemia. 
In the 26-week open-label trial comparing Victoza to sitagliptin, the incidence of hypoglycemic events defined as symptoms accompanied by a fingerstick glucose <56 mg/dL was comparable among the treatment groups (approximately 5%).
Table 5 Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in the 52-Week Monotherapy Trial and in the 26-Week Combination Therapy Trials

Victoza Treatment	Active Comparator	Placebo Comparator
Monotherapy	Victoza (N = 497)	Glimepiride (N = 248)	None
Patient not able to self-treat	0	0	-
Patient able to self-treat	9.7 (0.24)	25.0 (1.66)	-
Not classified	1.2 (0.03)	2.4 (0.04)	-
Add-on to Metformin	Victoza + Metformin (N = 724)	Glimepiride + Metformin (N = 242)	Placebo + Metformin (N = 121)
Patient not able to self-treat	0.1 (0.001)	0	0
Patient able to self-treat	3.6 (0.05)	22.3 (0.87)	2.5 (0.06)
Add-on to Victoza + Metformin	Insulin detemir + Victoza + Metformin (N = 163)	Continued Victoza + Metformin alone (N = 158*)	None
Patient not able to self-treat	0	0	-
Patient able to self-treat	9.2 (0.29)	1.3 (0.03)	-
Add-on to Glimepiride	Victoza + Glimepiride (N = 695)	Rosiglitazone + Glimepiride (N = 231)	Placebo + Glimepiride (N = 114)
Patient not able to self-treat	0.1 (0.003)	0	0
Patient able to self-treat	7.5 (0.38)	4.3 (0.12)	2.6 (0.17)
Not classified	0.9 (0.05)	0.9 (0.02)	0
Add-on to Metformin + Rosiglitazone	Victoza + Metformin + Rosiglitazone (N = 355)	None	Placebo + Metformin + Rosiglitazone (N = 175)
Patient not able to self-treat	0	-	0
Patient able to self-treat	7.9 (0.49)	-	4.6 (0.15)
Not classified	0.6 (0.01)	-	1.1 (0.03)
Add-on to Metformin + Glimepiride	Victoza + Metformin + Glimepiride (N = 230)	Insulin glargine + Metformin + Glimepiride (N = 232)	Placebo + Metformin + Glimepiride (N = 114)
Patient not able to self-treat	2.2 (0.06)	0	0
Patient able to self-treat	27.4 (1.16)	28.9 (1.29)	16.7 (0.95)
Not classified	0	1.7 (0.04)	0

One patient is an outlier and was excluded due to 25 hypoglycemic episodes that the patient was able to self-treat. This patient had a history of frequent hypoglycemia prior to the study.
In a pooled analysis of clinical trials, the incidence rate (per 1,000 patient-years) for malignant neoplasms (based on investigator-reported events, medical history, pathology reports, and surgical reports from both blinded and open-label study periods) was 10.9 for Victoza, 6.3 for placebo, and 7.2 for active comparator. After excluding papillary thyroid carcinoma events [see Adverse Reactions (6.1)], no particular cancer cell type predominated. Seven malignant neoplasm events were reported beyond 1 year of exposure to study medication, six events among Victoza-treated patients (4 colon, 1 prostate and 1 nasopharyngeal), no events with placebo and one event with active comparator (colon). Causality has not been established.
Laboratory Tests
Bilirubin
In the five clinical 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 clinical 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.
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. The long-term clinical effects of the increase in pulse rate have not been established [see Warnings and Precautions (5.7)].
6.2 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 (17.3) ]
• 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 (17.3) ]
• Angioedema and anaphylactic reactions. [see Contraindications (4), Warnings and Precautions (5.6) , Patient counseling Information (17.6) ]
• Allergic reactions: rash and pruritus
• Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [ see Warnings and Precautions (5.2) ]
7 DRUG INTERACTIONS
7.1 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.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category C.
There are no adequate and well-controlled studies of Victoza in pregnant women. Victoza should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Liraglutide has been shown to be teratogenic in rats at or above 0.8 times the human systemic exposures resulting from the maximum recommended human dose (MRHD) of 1.8 mg/day based on plasma area under the time-concentration curve (AUC). Liraglutide has been shown to cause reduced growth and increased total major abnormalities in rabbits at systemic exposures below human exposure at the MRHD based on plasma AUC.
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.
8.3 Nursing Mothers
It is not known whether Victoza is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for tumorigenicity shown for liraglutide in animal studies, a decision should be made whether to discontinue nursing or to discontinue Victoza, taking into account the importance of the drug to the mother. In lactating rats, liraglutide was excreted unchanged in milk at concentrations approximately 50% of maternal plasma concentrations.
8.4 Pediatric Use
Safety and effectiveness of Victoza have not been established in pediatric patients. Victoza is not recommended for use in pediatric patients.
8.5 Geriatric Use
In the Victoza clinical trials, a total of 797 (20%) of the patients were 65 years of age and over and 113 (2.8%) were 75 years of age and over. No overall differences in safety or effectiveness were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6 Renal Impairment
There is limited experience with Victoza in patients with mild, moderate, and severe renal impairment, including end-stage renal disease. However, 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)]. Victoza should be used with caution in this patient population. No dose adjustment of Victoza is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)].
8.7 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)].
8.8 Gastroparesis
Victoza slows gastric emptying. Victoza has not been studied in patients with pre-existing gastroparesis.
10 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.
11 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 solution. Each 1 mL of Victoza solution contains 6 mg of liraglutide. Each pre-filled pen contains a 3 mL solution of Victoza equivalent to 18 mg liraglutide (free-base, anhydrous) and the following inactive ingredients: disodium phosphate dihydrate, 1.42 mg; propylene glycol, 14 mg; phenol, 5.5 mg; and water for injection.
12 CLINICAL PHARMACOLOGY
12.1 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.
12.2 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.
12.3 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 34% 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.
13 NONCLINICAL TOXICOLOGY
13.1 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.
14 CLINICAL STUDIES
A total of 6090 patients with type 2 diabetes participated in 8 phase 3 trials. There were 5 double-blind (one of these trials had an open-label active control insulin glargine arm), randomized, controlled clinical trials, one of 52 weeks duration and four of 26 weeks duration. There were also three 26 week open-label trials; one comparing Victoza to twice-daily exenatide, one comparing Victoza to sitagliptin and one comparing Victoza+metformin+insulin detemir to Victoza+metformin alone. These multinational trials were conducted to evaluate the glycemic efficacy and safety of Victoza in type 2 diabetes as monotherapy and in combination with one or two oral anti-diabetic medications or insulin detemir. The 7 add-on combination therapy trials enrolled patients who were previously treated with anti-diabetic therapy, and approximately two-thirds of patients in the monotherapy trial also were previously treated with anti-diabetic therapy. In total, 272 (4%) of the 6090 patients in these 8 trials were new to anti-diabetic therapy. In these 8 clinical trials, patients ranged in age from 18-80 years old and 54% were men. Approximately 82% of patients were Caucasian, and 6% were Black. In the 5 trials where ethnicity was captured, 10% of patients were Hispanic/Latino (n=630).
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)].
14.1 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 6). 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.
Table 6 Results of a 52-week monotherapy trial*

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)†	-1.1	-0.8	-0.5
Difference from glimepiride arm (adjusted mean)†	-0.6‡	-0.3§
95% Confidence Interval	(-0.8, -0.4)	(-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)†	-26	-15	-5
Difference from glimepiride arm (adjusted mean)†	-20‡	-10§
95% Confidence Interval	(-29, -12)	(-19, -1)
Body Weight (kg) (Mean)
Baseline	92.6	92.1	93.3
Change from baseline (adjusted mean)†	-2.5	-2.1	+1.1
Difference from glimepiride arm (adjusted mean)†	-3.6‡	-3.2‡
95% Confidence Interval	(-4.3, -2.9)	(-3.9, -2.5)

Intent-to-treat population using last observation on study
Least squares mean adjusted for baseline value
p-value <0.0001
p-value <0.05

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)
14.2 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 7). 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.
Table 7 Results of a 26-week trial of Victoza as add-on to metformin

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)‡	-1.0	-1.0	+0.1	-1.0
Difference from placebo + metformin arm (adjusted mean)‡	-1.1§	-1.1§
95% Confidence Interval	(-1.3, -0.9)	(-1.3, -0.9)
Difference from glimepiride + metformin arm (adjusted mean)‡	0.0	0.0
95% Confidence Interval	(-0.2, 0.2)	(-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)‡	-30	-30	+7	-24
Difference from placebo + metformin arm (adjusted mean)‡	-38§	-37§
95% Confidence Interval	(-48, -27)	(-47, -26)
Difference from glimepiride + metformin arm (adjusted mean)‡	-7	-6
95% Confidence Interval	(-16, 2)	(-15, 3)
Body Weight (kg) (Mean)
Baseline	88.0	88.5	91.0	89.0
Change from baseline (adjusted mean)‡	-2.8	-2.6	-1.5	+1.0
Difference from placebo + metformin arm (adjusted mean)‡	-1.3¶	-1.1¶
95% Confidence Interval	(-2.2, -0.4)	(-2.0, -0.2)
Difference from glimepiride + metformin arm (adjusted mean)‡	-3.8§	-3.5§
95% Confidence Interval	(-4.5, -3.0)	(-4.3, -2.8)

Intent-to-treat population using last observation on study
For glimepiride, one-half of the maximal approved United States dose
Least squares mean adjusted for baseline value
p-value <0.0001
p-value <0.05
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 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 8). 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 8 Results of a 26-week open-label trial of Victoza Compared to Sitagliptin (both in combination with metformin)* 

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)† 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)† 95% Confidence Interval	-24‡ (-31, -16)	-19‡ (-26, -12)

Intent-to-treat population using last observation on study
Least 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.
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 9). 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 9 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 Victoza* 

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)† 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)† 95% Confidence Interval	-31‡ (-39, -23)

Intent-to-treat population using last observation on study
Least squares mean adjusted for baseline value
p-value <0.0001
Add-on to Sulfonylurea
In this 26-week trial, 1041 patients were randomized to Victoza 0.6 mg, Victoza 1.2 mg, Victoza 1.8 mg, placebo, or rosiglitazone 4 mg (one-half of the maximal approved dose in the United States), all as add-on to glimepiride. Randomization occurred after a 4-week run-in period consisting of an initial, 2-week, forced-glimepiride titration period followed by a maintenance period of another 2 weeks. During the titration period, doses of glimepiride were increased to 4 mg/day. The doses of glimepiride could be reduced (at the discretion of the investigator) from 4 mg/day to 3 mg/day or 2 mg/day (minimum) after randomization, in the event of unacceptable hypoglycemia or other adverse events.
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 10). 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 10 Results of a 26-week trial of Victoza as add-on to sulfonylurea* 

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)‡	-1.1	-1.1	+0.2	-0.4
Difference from placebo + glimepiride arm (adjusted mean)‡	-1.4§	-1.3§
95% Confidence Interval	(-1.6, -1.1)	(-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)‡	-29	-28	+18	-16
Difference from placebo + glimepiride arm (adjusted mean)‡	-47§	-46§
95% Confidence Interval	(-58, -35)	(-58, -35)
Body Weight (kg) (Mean)
Baseline	83.0	80.0	81.9	80.6
Change from baseline (adjusted mean)‡	-0.2	+0.3	-0.1	+2.1
Difference from placebo + glimepiride arm (adjusted mean)‡	-0.1	0.4
95% Confidence Interval	(-0.9, 0.6)	(-0.4, 1.2)

Intent-to-treat population using last observation on study
For rosiglitazone, one-half of the maximal approved United States dose.
Least squares mean adjusted for baseline value
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.
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 11). 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 11 Results of a 26-week trial of Victoza as add-on to metformin and sulfonylurea* 

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)‡	-1.3	-0.2	-1.1
Difference from placebo + metformin + glimepiride arm (adjusted mean)‡	-1.1§
95% Confidence Interval	(-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)‡	-28	+10	-32
Difference from placebo + metformin + glimepiride arm (adjusted mean)‡	-38§
95% Confidence Interval	(-46, -30)
Body Weight (kg) (Mean)
Baseline	85.8	85.4	85.2
Change from baseline (adjusted mean)‡	-1.8	-0.4	1.6
Difference from placebo + metformin + glimepiride arm (adjusted mean)‡	-1.4¶
95% Confidence Interval	(-2.1, -0.7)

Intent-to-treat population using last observation on study
For insulin glargine, optimal titration regimen was not achieved for 80% of patients.
Least squares mean adjusted for baseline value
p-value <0.0001
p-value <0.05
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.
Treatment with Victoza 1.8 mg resulted in statistically significant reductions in HbA1c and FPG relative to exenatide (Table 12). 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 12 Results of a 26-week open-label trial of Victoza versus Exenatide (both in combination with metformin and/or sulfonylurea)* 

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)†	-1.1	-0.8
Difference from exenatide arm (adjusted mean)†	-0.3‡
95% Confidence Interval	(-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)†	-29	-11
Difference from exenatide arm (adjusted mean)†	-18‡
95% Confidence Interval	(-25, -12)

Intent-to-treat population using last observation carried forward
Least squares mean adjusted for baseline value
p-value <0.0001
Add-on to Metformin and Thiazolidinedione
In this 26-week trial, 533 patients were randomized to Victoza 1.2 mg, Victoza 1.8 mg or placebo, all as add-on to rosiglitazone (8 mg) plus metformin (2000 mg). Patients underwent a 9 week run-in period (3-week forced dose escalation followed by a 6-week dose maintenance phase) with rosiglitazone (starting at 4 mg and increasing to 8 mg/day within 2 weeks) and metformin (starting at 500 mg with increasing weekly increments of 500 mg to a final dose of 2000 mg/day). Only patients who tolerated the final dose of rosiglitazone (8 mg/day) and metformin (2000 mg/day) and completed the 6-week dose maintenance phase were eligible for randomization into the trial.
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 13). 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 13 Results of a 26-week trial of Victoza as add-on to metformin and thiazolidinedione

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)†	-1.5	-1.5	-0.5
Difference from placebo + metformin + rosiglitazone arm (adjusted mean)†	-0.9‡	-0.9‡
95% Confidence Interval	(-1.1, -0.8)	(-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)†	-44	-40	-8
Difference from placebo + metformin + rosiglitazone arm (adjusted mean)†	-36‡	-32‡
95% Confidence Interval	(-44, -27)	(-41, -23)
Body Weight (kg) (Mean)
Baseline	94.9	95.3	98.5
Change from baseline (adjusted mean)†	-2.0	-1.0	+0.6
Difference from placebo + metformin + rosiglitazone arm (adjusted mean)†	-2.6‡	-1.6‡
95% Confidence Interval	(-3.4, -1.8)	(-2.4, -1.0)

Intent-to-treat population using last observation on study
Least squares mean adjusted for baseline value
p-value <0.0001
16 HOW SUPPLIED/STORAGE AND HANDLING
16.1 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.
16.2 Recommended Storage
Prior to first use, Victoza should be stored in a refrigerator between 36ºF to 46ºF (2ºC to 8ºC) (Table 14). 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 14 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

17 PATIENT COUNSELING INFORMATION
17.1 FDA-Approved Medication Guide
See separate leaflet.
17.2 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)].
17.3 Dehydration and Renal Failure
Patients treated with Victoza should be advised of the potential risk of dehydration due to gastrointestinal adverse reactions and take precautions to avoid fluid depletion. Patients should be informed of the potential risk for worsening renal function, which in some cases may require dialysis.
17.4 Pancreatitis
Patients should be informed 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)].
17.5 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.
17.6 Hypersensitivity Reactions
Patients should be informed that serious hypersensitivity reactions have been reported during postmarketing use of Victoza. If symptoms of hypersensitivity reactions occur, patients must stop taking Victoza and seek medical advice promptly [see Warnings and Precautions (5.6)].
17.7 Instructions
Patients should be informed of the potential risks and benefits of Victoza and of alternative modes of therapy. Patients should also be informed about the importance of adherence to dietary instructions, regular physical activity, periodic blood glucose monitoring and A1c testing, recognition and management of hypoglycemia and hyperglycemia, and assessment for diabetes complications. During periods of stress such as fever, trauma, infection, or surgery, medication requirements may change and patients should be advised to seek medical advice promptly.
Patients should be advised 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.
Physicians should instruct their patients to read the Patient Medication Guide before starting Victoza therapy and to reread each time the prescription is renewed. Patients should be instructed to inform their doctor or pharmacist if they develop any unusual symptom, or if any known symptom persists or worsens.
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, the patient should be advised 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)].
17.8 Laboratory Tests
Patients should be informed that response to all diabetic therapies should be monitored by periodic measurements of blood glucose and A1c levels, with a goal of decreasing these levels towards the normal range. A1c is especially useful for evaluating long-term glycemic control.
Date of Issue: March 9, 2015
Version: 8
Victoza® is a registered trademark of Novo Nordisk A/S.
Victoza® is covered by US Patent Nos. 6,268,343, 6,458,924, 7,235,627, 8,114,833 and other patents pending.
Victoza® Pen is covered by US Patent Nos. 6,004,297, RE 43,834, RE 41,956 and other patents pending.
包装规格
美国诺和诺德公司
Victoza®注射笔
VICTOZA PREFILLED PEN 2
VICTOZA PREFILLED PEN 3

Victoza®注射笔
3毫升x1支/盒（3支起订）
3毫升x2支/盒（2支起订）
3毫升x5支/盒

德国诺和诺德公司（Novo Nordisk Pharma GmbH）
2009年7月8日,，欧洲药品管理局（EMEA）人用药品委员会（CHMP）表决通过了对Victoza®的积极评价，建议颁发入市许可，将该药用于治疗2型糖尿病。
Victoza®是利拉鲁肽的商标名，它是第一个人胰高糖素样肽-1(GLP-1)类似物，每日皮下注射一次，用于治疗2型糖尿病。
对Victoza®的积极评价包括：
1、对于单独服用最大剂量的二甲双胍或磺脲类药物仍不能控制血糖的患者来说，Victoza®与二甲双胍或者与磺脲类药物联合使用，可改善血糖控制；
2、 对于即使采用“二甲双胍＋磺脲类药物”或“二甲双胍＋噻唑烷二酮”联合治疗也不能控制血糖的患者来说，Victoza®与“二甲双胍＋磺脲类药物”或者与“二甲双胍＋噻唑烷二酮”联合使用，可进一步改善血糖控制。
关于Victoza®
Victoza®是第一个人胰高糖素样肽-1(GLP-1)类似物，每日皮下注射一次，用于治疗2型糖尿病。患者血糖水平过高时，Victoza®可刺激胰岛素的分泌，降低食欲。2008年5月23日，诺和诺德公司向美国食品药品管理局提交了新药申请，向欧洲药品管理局提交了入市申请，请求他们批准将Victoza®用于治疗2型糖尿病。2008年7月14日还向日本有关当局提交了新药申请。