liraglutide

1 INDICATIONS AND USAGE VICTOZA is indicated:

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

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

Recommended Dosage Adult Patients

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

Recommendations Regarding Missed Dose

• Instruct patients who miss a dose of VICTOZA to resume the once daily dosage regimen as prescribed with the next scheduled dose. Do not administer an extra dose or increase the dose to make up for the missed dose.
• If more than 3 days have elapsed since the last VICTOZA dose, reinitiate VICTOZA at 0.6 mg once daily to reduce the risk of gastrointestinal adverse reactions associated with reinitiation of treatment. Upon reinitiation, VICTOZA should be titrated at the discretion of the healthcare provider.

Important Administration Instructions

• Inspect visually prior to each injection. Only use if solution is clear, colorless, and contains no particles.
• Inject VICTOZA subcutaneously once daily at any time of day, independently of meals.
• Inject VICTOZA subcutaneously in the abdomen, thigh or upper arm. No dosage adjustment is needed if changing the injection site and/or timing.
• Rotate injection sites within the same region in order to reduce the risk of cutaneous amyloidosis [see Adverse Reactions ].
• 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.

12.1 Mechanism of Action Liraglutide is an acylated human 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 to 2 minutes due to degradation by the ubiquitous endogenous enzymes, dipeptidyl peptidase 4 (DPP-4) 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-4 and NEP.

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

• Risk of Thyroid C-cell Tumors [see Warnings and Precautions ]
• Acute Pancreatitis [see Warnings and Precautions ]
• Hypoglycemia [see Warnings and Precautions ]
• Acute Kidney Injury Due to Volume Depletion [see Warnings and Precautions ]
• Severe Gastrointestinal Adverse Reactions [see Warnings and Precautions ]
• Hypersensitivity Reactions [see Warnings and Precautions ]
• Acute Gallbladder Disease [see Warnings and Precautions ]
• Pulmonary Aspiration During General Anesthesia or Deep Sedation [see Warnings and Precautions ]
• Most common adverse reactions (incidence ≥5%) in clinical trials are nausea, diarrhea, vomiting, decreased appetite, dyspepsia, constipation.
• Immunogenicity-related events, including urticaria, were more common among VICTOZA-treated patients (0.8%) than among comparator-treated patients (0.4%) in clinical trials. To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-877-484-2869 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Common Adverse Reactions The safety of VICTOZA in patients with type 2 diabetes mellitus was evaluated in 5 glycemic control, placebo-controlled trials in adults and one trial of 52 weeks duration in pediatric patients 10 years of age and older [see Clinical Studies ] . The data in Table 1 reflect exposure of 1,673 adult patients to VICTOZA and a mean duration of exposure to VICTOZA of 37.3 weeks. The mean age of adult patients was 58 years, 4% were 75 years or older and 54% were male. The population was 79% White, 6% Black or African American, 13% Asian; 4% were of Hispanic or Latino ethnicity. At baseline the population had diabetes for an average of 9 years and a mean HbA 1c of 8.4%. Baseline estimated renal function was normal or mildly impaired in 88% and moderately impaired in 12% of the pooled population. Table 1 shows common adverse reactions in adults, excluding hypoglycemia, associated with the use of VICTOZA for the treatment of type 2 diabetes mellitus. These adverse reactions occurred more commonly on VICTOZA than on placebo and occurred in at least 5% of patients treated with VICTOZA. Overall, the type, and severity of adverse reactions in pediatric patients 10 years of age and older and above were comparable to that observed in the adult population. Table 1. Adverse reactions reported in ≥5% of Adult Patients Treated with VICTOZA for Type 2 Diabetes Mellitus Placebo N=661 Liraglutide 1.2 mg N= 645 Liraglutide 1.8 mg N= 1024 Adverse Reaction (%) (%) (%) Nausea 5 18 20 Diarrhea 4 10 12 Headache 7 11 10 Nasopharyngitis 8 9 10 Vomiting 2 6 9 Decreased appetite 1 10 9 Dyspepsia 1 4 7 Upper Respiratory Tract Infection 6 7 6 Constipation 1 5 5 Back Pain 3 4 5 Cumulative proportions were calculated combining studies using Cochran-Mantel-Haenszel weights. In an analysis of placebo- and active-controlled trials, the types and frequency of common adverse reactions, excluding hypoglycemia, were similar to those listed in Table 1 . Other Adverse Reactions Gastrointestinal Adverse Reactions In the pool of 5 glycemic control, placebo-controlled adult clinical trials, withdrawals due to gastrointestinal adverse reactions, occurred in 4.3% of VICTOZA-treated patients and 0.5% of placebo-treated patients. Severe gastrointestinal adverse reactions were reported more frequently among patients receiving VICTOZA (1.2 mg 4.4%, 1.8 mg 4.2%) than placebo (1.1%). Withdrawal due to gastrointestinal adverse events mainly occurred during the first 2 to 3 months of the trials. Injection site reactions Injection site reactions (e.g., injection site rash, erythema) were reported in approximately 2% of VICTOZA-treated adult patients in the five double-blind, glycemic control trials of at least 26 weeks duration. Less than 0.2% of VICTOZA-treated patients discontinued due to injection site reactions. Hypoglycemia In 5 adult glycemic control, placebo-controlled clinical trials of at least 26 weeks duration, hypoglycemia requiring the assistance of another person for treatment occurred in 8 VICTOZA-treated patients (7.5 events per 1,000 patient-years). Of these 8 VICTOZA-treated patients, 7 patients were concomitantly using a sulfonylurea. Table 2. Adult Incidence (%) and Rate (episodes/patient year) of Hypoglycemia in 26-Week Combination Therapy Placebo-controlled Trials Placebo Comparator VICTOZA Treatment Add-on to Metformin Placebo + Metformin (N=121) VICTOZA + Metformin (N=724) Patient not able to self-treat 0 0.1 Patient able to self-treat 2.5 3.6 Add-on to Glimepiride Placebo + Glimepiride (N=114) VICTOZA + Glimepiride (N=695) Patient not able to self-treat 0 0.1 Patient able to self-treat 2.6 7.5 Not classified 0 0.9 Add-on to Metformin + Rosiglitazone Placebo + Metformin + Rosiglitazone (N=175) VICTOZA + Metformin + Rosiglitazone (N=355) Patient not able to self-treat 0 0 Patient able to self-treat 4.6 7.9 Not classified 1.1 0.6 Add-on to Metformin + Glimepiride Placebo + Metformin + Glimepiride (N=114) VICTOZA + Metformin + Glimepiride (N=230) Patient not able to self-treat 0 2.2 Patient able to self-treat 16.7 27.4 Not classified 0 0 “Patient not able to self-treat” is defined as an event requiring the assistance of another person for treatment. In a 26-week placebo-controlled clinical trial in pediatric patients 10 years of age and older with a 26-week open-label extension, 21.2% of VICTOZA-treated patients (mean age 14.6 years) with type 2 diabetes mellitus, had hypoglycemia with a blood glucose 20 ng/L occurred in 0.7% of VICTOZA-treated patients, 0.3% of placebo-treated patients, and 0.5% of active-comparator-treated patients. The clinical significance of these findings is unknown. Lipase and Amylase In one adult glycemic control trial in renal impairment patients, a mean increase of 33% for lipase and 15% for amylase from baseline was observed for VICTOZA-treated patients while placebo-treated patients had a mean decrease in lipase of 3% and a mean increase in amylase of 1%. In the LEADER trial, serum lipase and amylase were routinely measured. Among adult VICTOZA-treated patients, 7.9% had a lipase value at any time during treatment of greater than or equal to 3 times the upper limit of normal compared with 4.5% of placebo-treated patients, and 1% of VICTOZA-treated patients had an amylase value at any time during treatment of greater than or equal to 3 times the upper limit of normal versus 0.7% of placebo-treated patients. The clinical significance of elevations in lipase or amylase with VICTOZA is unknown in the absence of other signs and symptoms of pancreatitis [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 in adult patients treated with VICTOZA compared to placebo. 6.2 Postmarketing Experience The following additional adverse reactions have been reported during post-approval use of VICTOZA. Because these events are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
• Gastrointestinal: Acute pancreatitis; hemorrhagic and necrotizing pancreatitis sometimes resulting in death; ileus, intestinal obstruction, severe constipation including fecal impaction, nausea, vomiting and diarrhea leading to dehydration
• Hepatobiliary: Elevations of liver enzymes, hyperbilirubinemia, cholestasis, cholecystitis, cholelithiasis requiring cholecystectomy, hepatitis
• Hypersensitivity: Angioedema, anaphylactic reactions, pruritus
• Neoplasms: Medullary thyroid carcinoma
• Neurologic: Dysgeusia, dizziness, dysesthesia
• Pulmonary: Pulmonary aspiration has occurred in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation.
• Renal: Acute renal failure or worsening of chronic renal failure, sometimes requiring hemodialysis; and increased serum creatinine
• Skin and subcutaneous tissue: Cutaneous amyloidosis, alopecia

Effects of delayed gastric emptying on oral medications: VICTOZA delays gastric emptying and may impact absorption of concomitantly administered oral medications. 7.1 Effects of Delayed Gastric Emptying on 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 [see Clinical Pharmacology ] . Nonetheless, caution should be exercised when oral medications are concomitantly administered with VICTOZA. 7.2 Concomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin VICTOZA stimulates insulin release in the presence of elevated blood glucose concentrations. Patients receiving VICTOZA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin may have an increased risk of hypoglycemia, including severe hypoglycemia. When initiating VICTOZA, consider reducing the dose of concomitantly administered insulin secretagogues (such as sulfonylureas) or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions , Adverse Reactions ].

Pregnancy: VICTOZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.1 Pregnancy Risk Summary Based on animal reproduction studies, there may be risks to the fetus from exposure to VICTOZA during pregnancy. VICTOZA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal reproduction studies identified increased adverse developmental outcomes from exposure during pregnancy. Liraglutide exposure was associated with early embryonic deaths and an imbalance in some fetal abnormalities in pregnant rats administered liraglutide during organogenesis at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 1.8 mg/day. In pregnant rabbits administered liraglutide during organogenesis, decreased fetal weight and an increased incidence of major fetal abnormalities were seen at exposures below the human exposures at the MRHD (see Animal Data) . The estimated background risk of major birth defects for women with uncontrolled pre-gestational diabetes (Hemoglobin A 1c >7) is 6 to 10%. The major birth defect rate has been reported to be as high as 20 to 25% in women with a Hemoglobin A 1c >10. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity. Animal Data Female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide beginning 2 weeks before mating through gestation day 17 had estimated systemic exposures 0.8-, 3-, and 11-times the human exposure at the MRHD based on plasma AUC comparison. The number of early embryonic deaths in the 1 mg/kg/day group increased slightly. Fetal abnormalities and variations in kidneys and blood vessels, irregular ossification of the skull, and a more complete state of ossification occurred at all doses. Mottled liver and minimally kinked ribs occurred at the highest dose. The incidence of fetal malformations in liraglutide-treated groups exceeding concurrent and historical controls were misshapen oropharynx and/or narrowed opening into larynx at 0.1 mg/kg/day and umbilical hernia at 0.1 and 0.25 mg/kg/day. Pregnant rabbits given subcutaneous doses of 0.01, 0.025 and 0.05 mg/kg/day liraglutide from gestation day 6 through day 18 inclusive, had estimated systemic exposures less than the human exposure at the MRHD of 1.8 mg/day at all doses, based on plasma AUC. Liraglutide decreased fetal weight and dose-dependently increased the incidence of total major fetal abnormalities at all doses. The incidence of malformations exceeded concurrent and historical controls at 0.01 mg/kg/day (kidneys, scapula), ≥0.01 mg/kg/day (eyes, forelimb), 0.025 mg/kg/day (brain, tail and sacral vertebrae, major blood vessels and heart, umbilicus), ≥0.025 mg/kg/day (sternum) and at 0.05 mg/kg/day (parietal bones, major blood vessels). Irregular ossification and/or skeletal abnormalities occurred in the skull and jaw, vertebrae and ribs, sternum, pelvis, tail, and scapula; and dose-dependent minor skeletal variations were observed. Visceral abnormalities occurred in blood vessels, lung, liver, and esophagus. Bilobed or bifurcated gallbladder was seen in all treatment groups, but not in the control group. In pregnant female rats given subcutaneous doses of 0.1, 0.25 and 1 mg/kg/day liraglutide from gestation day 6 through weaning or termination of nursing on lactation day 24, estimated systemic exposures were 0.8-, 3-, and 11-times human exposure at the MRHD of 1.8 mg/day, based on plasma AUC. A slight delay in parturition was observed in the majority of treated rats. Group mean body weight of neonatal rats from liraglutide-treated dams was lower than neonatal rats from control group dams. Bloody scabs and agitated behavior occurred in male rats descended from dams treated with 1 mg/kg/day liraglutide. Group mean body weight from birth to postpartum day 14 trended lower in F 2 generation rats descended from liraglutide-treated rats compared to F 2 generation rats descended from controls, but differences did not reach statistical significance for any group. 8.2 Lactation Risk Summary There are no data on the presence of VICTOZA in human milk, the effects on the breastfed infant, or the effects on milk production. Liraglutide was present in milk of lactating rats (see Data) . Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VICTOZA and any potential adverse effects on the breastfed infant from VICTOZA or from the underlying maternal condition. Data In lactating rats, liraglutide was present unchanged in milk at concentrations approximately 50% of maternal plasma concentrations. 8.4 Pediatric Use The safety and effectiveness of VICTOZA as an adjunct to diet and exercise to improve glycemic control in type 2 diabetes mellitus have been established in pediatric patients 10 years of age and older. Use of VICTOZA for this indication is supported by a 26-week placebo-controlled clinical trial and a 26-week open-label extension in 134 pediatric patients 10 to 17 years of age with type 2 diabetes mellitus, a pediatric pharmacokinetic study, and studies in adults with type 2 diabetes mellitus [see Clinical Pharmacology and Clinical Studies ] . The risk of hypoglycemia was higher with VICTOZA in pediatric patients regardless of insulin and/or metformin use [see Adverse Reactions ] . The safety and effectiveness of VICTOZA have not been established in pediatric patients less than 10 years of age. 8.5 Geriatric Use In the VICTOZA treatment arms of the glycemic control trials, a total of 832 (19.3%) of the patients were 65 to 74 years of age and 145 (3.4%) were 75 years of age and over [see Clinical Studies ] . In the VICTOZA treatment arm of the LEADER trial [see Clinical Studies ] , a total of 1738 (37.2%) patients were 65 to 74 years of age, 401 (8.6%) were 75 to 84 years of age, and 17 (0.4%) were 85 years of age or older at baseline. No overall differences in safety or effectiveness for VICTOZA have been observed between patients 65 years of age and older and younger patients. 8.6 Renal Impairment No dose adjustment of VICTOZA is recommended for patients with renal impairment [see Clinical Pharmacology ]. The safety and efficacy of VICTOZA was evaluated in a 26-week clinical study that included patients with moderate renal impairment (eGFR 30 to 60 mL/min/1.73 m 2 ) [see Clinical Studies ]. In the VICTOZA treatment arm of the LEADER trial [see Clinical Studies ] , 1,932 (41.4%) patients had mild renal impairment, 999 (21.4%) patients had moderate renal impairment and 117 (2.5%) patients had severe renal impairment at baseline. No overall differences in safety or efficacy were seen in these patients compared to patients with normal renal function. There is limited experience with VICTOZA in patients with end stage renal disease. 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 ] .