Liraglutide [rDNA] Injection

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).

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.

Storage And Handling

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.

Prior to first use, VICTOZA should be stored in a refrigerator between 36°F to 46°F (2°C to 8°C) (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

Manufactured by: Novo Nordisk A/S, DK-2880 Bagsvaerd, Denmark. Revised: Aug 2017

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

• Risk of Thyroid C-cell Tumors [see WARNINGS AND PRECAUTIONS]
• Pancreatitis [see WARNINGS AND PRECAUTIONS]
• Use with Medications Known to Cause Hypoglycemia [see WARNINGS AND PRECAUTIONS]
• Renal Impairment [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity Reactions [see WARNINGS AND PRECAUTIONS]

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]. 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

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

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 (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 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

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.

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], 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) n VICTOZA-treated and 0.7% (1.9 cases per 1000 patient years of observation) in placebo-treated patients.

Laboratory Tests

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, 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.

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].

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 antiliraglutide 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], 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]
• Dehydration resulting from nausea, vomiting and diarrhea. [see WARNINGS AND PRECAUTIONS and PATIENT INFORMATION]
• Increased serum creatinine, acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis. [see WARNINGS AND PRECAUTIONS and PATIENT INFORMATION]
• Angioedema and anaphylactic reactions. [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, PATIENT INFORMATION]
• Allergic reactions: rash and pruritus
• Acute pancreatitis, hemorrhagic and necrotizing pancreatitis sometimes resulting in death [see WARNINGS AND PRECAUTIONS]
• Hepatobiliary disorders: elevations of liver enzymes, hyperbilirubinemia, cholestasis, hepatitis [see ADVERSE REACTIONS]

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.

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 Pharmacokinetics].

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.

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

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.

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

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

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%.

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%).

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.

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

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].

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 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 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.

VICTOZA has not been studied in pediatric patients [see Use In Specific Populations].

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].

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].

Drug Interactions

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

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.

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.

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.

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.

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.

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.

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.

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.

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].

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

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)

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 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

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]. 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

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

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 prespecified 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 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

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 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

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®
(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
  • blurred vision
  • anxiety, irritability, or mood changes
  • sweating
  • slurred speech
  • hunger
  • confusion or drowsiness
  • shakiness
  • weakness
  • headache
  • fast heartbeat
  • 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.
• serious allergic 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
  • Fainting or feeling dizzy
  • Problems breathing or swallowing
  • Very rapid heartbeat
  • Severe rash or itching
• 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

Instructions for Use

Victoza (liraglutide) 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 1-877-4842869.

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 36°F to 46°F (2°C to 8°C).
• 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 59°F to 86°F (15°C to 30°C), or in a refrigerator at 36°F to 46°F (2°C to 8°C).
• When carrying the pen away from home, store the pen at a temperature between 59°F to 86°F (15°C to 30°C).
• If Victoza has been exposed to temperatures above 86°F (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.

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