Liraglutide 6 mg/mL Injection — NDC 71288-563-85 (Billing 71288-0563-85)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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.

12.2Pharmacodynamics Liraglutide’s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as liraglutide injection 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 liraglutide or placebo. Compared to placebo, the postprandial plasma glucose AUC 0-300min was 35% lower after liraglutide 1.2 mg and 38% lower after liraglutide 1.8 mg.

Glucose-dependent insulin secretion The effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) liraglutide on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes mellitus 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 Liraglutide 7.5 mcg/kg (~ 0.7 mg) or Placebo in Patients with Type 2 Diabetes Mellitus (N=10) During Graded Glucose Infusion Glucagon secretion Liraglutide lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of liraglutide 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations. Gastric emptying Liraglutide causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Cardiac Electrophysiology (QTc) The effect of liraglutide injection on cardiac repolarization was tested in a QTc study. Liraglutide at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation. Figure 2

12.3Pharmacokinetics Absorption Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8 to 12 hours post dosing. The mean peak (C max ) 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, C max and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg.

At 1.8 mg liraglutide, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC 0-∞ was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC 0-∞ from thigh was 22% lower than that from abdomen.

However, liraglutide exposures were considered comparable among these three subcutaneous inj… [Excerpted — this section continues on DailyMed.]

12.1Mechanism 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.

12.3Pharmacokinetics Absorption Following subcutaneous administration, maximum concentrations of liraglutide are achieved at 8 to 12 hours post dosing. The mean peak (C max ) 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, C max and AUC of liraglutide increased proportionally over the therapeutic dose range of 0.6 mg to 1.8 mg.

At 1.8 mg liraglutide, the average steady state concentration of liraglutide over 24 hours was approximately 128 ng/mL. AUC 0-∞ was equivalent between upper arm and abdomen, and between upper arm and thigh. AUC 0-∞ 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 liraglutide 0.6 mg is approximately 13 L.

The mean volume of distribution after intravenous administration of liraglutide injection is

0.07L/kg. Liraglutide is extensively bound to plasma protein (>98%). Elimination The mean apparent clearance following subcutaneous administration of a single dose of liraglutide is approximately

1.2L/h with an elimination half-life of approximately 13 hours. Metabolism During the initial 24 hours following administration of a single [ 3 H]-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.

Excretion Following a [ 3 H]-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 to 8 days.

Specific Populations Geriatric Patients Age had no effect on the pharmacokinetics of liraglutide 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 )] . Pediatric Patients A population pharmacokinetic analysis was conducted for liraglutide using data from 72 pediatric patients (10 to 17 years of age) with type 2 diabetes mellitus. The pharmacokinetic profile of liraglutide in pediatric patients was consistent with that in adults.

Male and Female Patients Based on the results of population pharmacokinetic analyses, females have 25% lower weight-adjusted clearance of liraglutide compared to males. Race or Ethnic Groups Race and ethnicity had no effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic analyses that included White, Black or African American, Asian and Hispanic or Latino/Non-Hispanic or Latino subjects. Body Weight Body weight significantly affects the pharmacokinetics of liraglutide 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 liraglutide provided adequate systemic exposures over the body weight range of 40 kg to 160 kg evaluated in the clinical trials. Liraglutide was not studied in patients with body weight >160 kg.

Patients with R enal Impairment The single-dose pharmacokinetics of liraglutide were evaluated in patients with varying degrees of renal impairment. Patients 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 an… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Liraglutide’s pharmacodynamic profile is consistent with its pharmacokinetic profile observed after single subcutaneous administration as liraglutide injection 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 liraglutide or placebo. Compared to placebo, the postprandial plasma glucose AUC 0-300min was 35% lower after liraglutide 1.2 mg and 38% lower after liraglutide 1.8 mg.

Glucose-dependent insulin secretion The effect of a single dose of 7.5 mcg/kg (~ 0.7 mg) liraglutide on insulin secretion rates (ISR) was investigated in 10 patients with type 2 diabetes mellitus 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 Liraglutide 7.5 mcg/kg (~ 0.7 mg) or Placebo in Patients with Type 2 Diabetes Mellitus (N=10) During Graded Glucose Infusion Glucagon secretion Liraglutide lowered blood glucose by stimulating insulin secretion and lowering glucagon secretion. A single dose of liraglutide 7.5 mcg/kg (~ 0.7 mg) did not impair glucagon response to low glucose concentrations. Gastric emptying Liraglutide causes a delay of gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Cardiac Electrophysiology (QTc) The effect of liraglutide injection on cardiac repolarization was tested in a QTc study. Liraglutide at steady state concentrations with daily doses up to 1.8 mg did not produce QTc prolongation. Figure 2

14 CLINICAL STUDIES

14.1Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus In glycemic control trials in adults, liraglutide injection has been studied as monotherapy and in combination with one or two oral anti-diabetic medications or basal insulin. In each of the placebo controlled trials, treatment with liraglutide produced clinically and statistically significant improvements in hemoglobin A 1c and fasting plasma glucose (FPG) compared to placebo. All liraglutide-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. Liraglutide 0.6 mg is not effective for glycemic control and is intended only as a starting dose to reduce gastrointestinal intolerance [see Dosage and Administration (2 )] . Monotherapy In this 52-week trial, 746 adult patients with type 2 diabetes mellitus were randomized to liraglutide 1.2 mg, liraglutide 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 liraglutide 1.8 mg and 1.2 mg resulted in a statistically significant reduction in HbA 1c compared to glimepiride ( Table 3 ). The percentage of patients who discontinued due to ineffective therapy was 3.6% in the liraglutide 1.8 mg treatment group, 6% in the liraglutide 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% of Hispanic or Latino ethnicity. The mean BMI was 33.1 kg/m 2 .

Table 3. Results of a 52-week Monotherapy Trial in Adults with Type 2 Diabetes Mellitus a Liraglutide 1 .8 mg Liraglutide 1.2 mg Glimepiride 8 mg Intent-to-Treat Population (N) 246 251 248 HbA 1c (%) (Mean) Baseline 8.2 8.2

8.2Change from baseline (adjusted mean) b -1.1 -0.8 -0.5 Difference from glimepiride arm (adjusted mean) b -0.6** -0.3* 95% Confidence Interval (-0.8, -0.4) (-0.5, -0.1) Percentage of patients achieving HbA 1c <7% 51 43 28 Fasting Plasma Glucose (mg/dL) (Mean) Baseline 172 168 172 Change from baseline (adjusted mean) b -26 -15 -5 Difference from glimepiride arm (adjusted mean) b -20** -10* 95% Confidence Interval (-29, -12) (-19, -1) Body Weight (kg) (Mean) Baseline 92.6 92.1

93.3Change from baseline (adjusted mean) b -2.5 -2.1 +1.1 Difference from glimepiride arm (adjusted mean) b -3.6** -3.2** 95% Confidence Interval (-4.3, -2.9) (-3.9, -2.5) a Intent-to-treat population using last observation on study b Least squares mean adjusted for baseline value * p-value <0.05 ** p-value <0.0001 Figure 3. Mean HbA 1c for Adult Patients with Type 2 Diabetes Mellitus who Completed the 52-week Trial and for the Last Observation Carried Forward (LOCF, intent-to-treat) Data at Week 52 (Monotherapy) Combination Therapy Add-on to Metformin In this 26-week trial, 1,091 adult patients with type 2 diabetes mellitus were randomized to liraglutide 0.6 mg, liraglutide 1.2 mg, liraglutide 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 2,000 mg/day. Treatment with liraglutide 1.2 mg and 1.8 mg as add-on to metformin resulted in a significant mean HbA 1c reduction relative to placebo add-on to metformin and resulted in a similar mean HbA 1c reduction relative to glimepiride 4 mg add-on to metformin ( Table 4 ).

The percentage of patients who discontinued due to ineffective therapy was 5.4% in the liraglutide 1.8 mg + metformin treatment group, 3.3% in the liraglutide 1.2 mg + metfor… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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, and 3 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 and the 3 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 per 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 per 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 , 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 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 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 mg/kg/day.

Reduced body weight gain and food consumption were observed in females at the 1 mg/kg/day dose.