Exenatide 250 ug/mL Injection, 1 cartridge — NDC 70121-1685-1 (Billing 70121-1685-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The amino acid sequence of exenatide partially overlaps that of human GLP-1.

Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro . This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

12.2Pharmacodynamics Glucose-Dependent Insulin Secretion Exenatide has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, exenatide does not impair the normal glucagon response to hypoglycemia.

First-Phase Insulin Response In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the “first-phase insulin response,” is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes.

Administration of exenatide at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with exenatide compared with saline (p < 0.001 for both). Figure 1: Mean (+SEM) Insulin Secretion Rate during Infusion of Exenatide or Saline in Patients with Type 2 Diabetes and during Infusion of Saline in Healthy Subjects Glucagon Secretion In patients with type 2 diabetes, exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia.

Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand. Gastric Emptying Exenatide slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation. Food Intake In both animals and humans, administration of exenatide has been shown to reduce food intake.

Postprandial Glucose In patients with type 2 diabetes, exenatide reduces postprandial plasma glucose concentrations (Figure 2). Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of Exenatide a Treatment in Patients with Type 2 Diabetes Treated with Metformin, a Sulfonylurea, or Both (N = 54) Fasting Glucose In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of exenatide. Plasma glucose concentrations were significantly reduced with exenatide compared with placebo (Figure 3).

Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of Exenatide a or Placebo in Fasting Patients with Type 2 Diabetes (N = 12) Cardiac Electrophysiology The effect of exenatide 10 mcg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was belo… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Incretins, such as glucagon-like peptide-1 (GLP-1), enhance glucose-dependent insulin secretion and exhibit other antihyperglycemic actions following their release into the circulation from the gut. Exenatide is a GLP-1 receptor agonist that enhances glucose-dependent insulin secretion by the pancreatic beta-cell, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The amino acid sequence of exenatide partially overlaps that of human GLP-1.

Exenatide has been shown to bind and activate the human GLP-1 receptor in vitro . This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide improves glycemic control by reducing fasting and postprandial glucose concentrations in patients with type 2 diabetes through the actions described below.

12.3Pharmacokinetics Absorption Following SC administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 hours. The mean peak exenatide concentration (C max ) was 211 pg/mL and overall mean area under the time-concentration curve (AUC 0-inf ) was 1,036 pg•h/mL following SC administration of a 10-mcg dose of exenatide. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 mcg to 10 mcg.

The C max values increased less than proportionally over the same range. Similar exposure is achieved with SC administration of exenatide in the abdomen, thigh, or upper arm. Distribution The mean apparent volume of distribution of exenatide following SC administration of a single-dose of exenatide is

28.3L. Metabolism and Elimination Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide in humans is

9.1L/hour and the mean terminal half-life is 2.4 hours. These pharmacokinetic characteristics of exenatide are independent of the dose. In most individuals, exenatide concentrations are measurable for approximately 10 hours post-dose.

Drug Interactions Acetaminophen When 1,000 mg acetaminophen elixir was given with 10 mcg exenatide (0 hour) and 1 hour, 2 hours and 4 hours after exenatide injection, acetaminophen AUCs were decreased by 21%, 23%, 24% and 14%, respectively; C max was decreased by 37%, 56%, 54% and 41%, respectively; T max was increased from 0.6 hour in the control period to 0.9 hour, 4.2 hours, 3.3 hours and 1.6 hours, respectively. Acetaminophen AUC, C max and T max were not significantly changed when acetaminophen was given 1 hour before exenatide injection.

Digoxin Administration of repeated doses of exenatide (10 mcg BID) 30 minutes before oral digoxin (0.25 mg once daily) decreased the C max of digoxin by 17% and delayed the T max of digoxin by approximately 2.5 hours; however, the overall steady-state pharmacokinetic exposure (e.g., AUC) of digoxin was not changed. Lovastatin Administration of exenatide (10 mcg BID) 30 minutes before a single oral dose of lovastatin (40 mg) decreased the AUC and C max of lovastatin by approximately 40% and 28%, respectively, and delayed the T max by about 4 hours compared with lovastatin administered alone.

In the 30-week controlled clinical trials of exenatide, the use of exenatide in patients already receiving HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles compared to baseline. Lisinopril In patients with mild to moderate hypertension stabilized on lisinopril (5 mg/day to 20 mg/day), exenatide (10 mcg BID) did not alter steady-state C max or AUC of lisinopril. Lisinopril steady-state T max was delayed by 2 hours.

There were no changes in 24-hour mean systolic and diastolic blood pressure. Oral Contraceptives The effect of exenatide (10 mcg BID) on single and on multiple-doses of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied in healthy female subjects. Repeated daily doses of the oral contraceptive (OC) given 30 minutes after exenatide administration decreased the C max of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively and delayed the T max of ethinyl estradiol and levonorgestrel by 3.0 hours and 3.5 hours, respectively, as compared to the oral contraceptive administered alone.

Administration of repeated daily doses of the OC one hour prior to exenatide administration decreased the mean C max of ethinyl estradiol by 15% but the mean C max of levonorgestrel was not significantly changed as compared to when the OC was given alone. Exenatide did not alter the mean trough concentrations of levonorgestrel after repeated daily dosing of the oral contraceptive for both regimens. However, the mean trough concentration of ethinyl estradiol was increased by 20% when the OC was adminis… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Glucose-Dependent Insulin Secretion Exenatide has acute effects on pancreatic beta-cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. However, exenatide does not impair the normal glucagon response to hypoglycemia.

First-Phase Insulin Response In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the “first-phase insulin response,” is characteristically absent in patients with type 2 diabetes. The loss of the first-phase insulin response is an early beta-cell defect in type 2 diabetes.

Administration of exenatide at therapeutic plasma concentrations restored first-phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (Figure 1). Both first-phase insulin secretion and second-phase insulin secretion were significantly increased in patients with type 2 diabetes treated with exenatide compared with saline (p < 0.001 for both). Figure 1: Mean (+SEM) Insulin Secretion Rate during Infusion of Exenatide or Saline in Patients with Type 2 Diabetes and during Infusion of Saline in Healthy Subjects Glucagon Secretion In patients with type 2 diabetes, exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia.

Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand. Gastric Emptying Exenatide slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation. Food Intake In both animals and humans, administration of exenatide has been shown to reduce food intake.

Postprandial Glucose In patients with type 2 diabetes, exenatide reduces postprandial plasma glucose concentrations (Figure 2). Figure 2: Mean (+SEM) Postprandial Plasma Glucose Concentrations on Day 1 of Exenatide a Treatment in Patients with Type 2 Diabetes Treated with Metformin, a Sulfonylurea, or Both (N = 54) Fasting Glucose In a single-dose crossover study in patients with type 2 diabetes and fasting hyperglycemia, immediate insulin release followed injection of exenatide. Plasma glucose concentrations were significantly reduced with exenatide compared with placebo (Figure 3).

Figure 3: Mean (+SEM) Serum Insulin and Plasma Glucose Concentrations Following a One-Time Injection of Exenatide a or Placebo in Fasting Patients with Type 2 Diabetes (N = 12) Cardiac Electrophysiology The effect of exenatide 10 mcg subcutaneously on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) crossover thorough QTc study in 62 healthy subjects. In this study with demonstrated ability to detect small effects, the upper bound of the 90% confidence interval for the largest placebo-adjusted, baseline-corrected QTc was below 10 msec.

Thus, exenatide (10 mcg single-dose) was not associated with clinically meaningful prolongation of the QTc interval. 10 10 10

14 CLINICAL STUDIES Exenatide has been studied as monotherapy and in combination with metformin, a sulfonylurea, a thiazolidinedione, a combination of metformin and a sulfonylurea, a combination of metformin and a thiazolidinedione, or in combination with insulin glargine with or without metformin and/or thiazolidinedione.

14.1Monotherapy In a randomized, double-blind, placebo-controlled trial of 24 weeks duration, exenatide 5 mcg BID (n=77), exenatide 10 mcg BID (n=78), or placebo BID (n=77) was used as monotherapy in patients with entry HbA 1c ranging from 6.5% to 10%. All patients assigned to exenatide initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive exenatide 5 mcg BID or had their dose increased to 10 mcg BID.

Patients assigned to placebo received placebo BID throughout the trial. Exenatide or placebo was injected subcutaneously before the morning and evening meals. The majority of patients (68%) were White, 26% were West Asian, 3% were Hispanic or Latino ethnicity, 3% were Black or African American and 0.4% were of East Asian ethnicity.

The primary endpoint was the change in HbA 1c from baseline to Week 24 (or the last value at time of early discontinuation). Compared to placebo, exenatide 5 mcg BID and 10 mcg BID resulted in statistically significant reductions in HbA 1c from baseline at Week 24 (Table 7). Table 7: Results of 24-Week Placebo-Controlled Trial of Exenatide used as Monotherapy Placebo BID Exenatide 5 mcg BID Exenatide 10 mcg * BID Intent-to-Treat Population (N) 77 77 78 HbA 1c (%), Mean Baseline 7.8 7.9

7.8Change at Week 24 † -0.2 -0.7 -0.9 Difference from placebo † (95% CI) -0.5 [-0.9, -0.2] ‡ -0.7 [-1.0, -0.3] Proportion Achieving HbA 1c < 7% 38% 48% 53% Body Weight (kg), Mean Baseline 86.1 85.1

86.2Change at Week 24 † -1.5 -2.7 -2.9 Difference from placebo † (95% CI) -1.3 [-2.3, -0.2] -1.5 [-2.5, -0.4] Fasting Serum Glucose § (mg/dL), Mean Baseline 159 166 155 Change at Week 24 † -5 -17 -19 Difference from placebo † (95% CI) -12 [-23.2, -1.3] -14 [-24.5, -2.5] * Exenatide 5 mcg twice daily (BID) for 1 month followed by 10 mcg BID for 5 months before the morning and evening meals. † Least squares means are adjusted for screening HbA 1c strata and baseline value of the dependent variable. ‡ p < 0.01, treatment vs. placebo. § Measured using the hexokinase-based glucose method.

BID = twice daily. On average, there were no adverse effects of exenatide on blood pressure or lipids.

14.2Combination Therapy with Oral Antihyperglycemic Medicines Three 30-week, double-blind, placebo-controlled trials were conducted to evaluate the safety and efficacy of exenatide in patients with type 2 diabetes whose glycemic control was inadequate with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea. In addition, a 16-week, placebo-controlled trial was conducted where exenatide was added to existing thiazolidinedione (pioglitazone or rosiglitazone) treatment, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control.

In the 30-week trials, after a 4-week placebo lead-in period, patients were randomly assigned to receive exenatide 5 mcg BID, exenatide 10 mcg BID, or placebo BID before the morning and evening meals, in addition to their existing oral antidiabetic agent. All patients assigned to exenatide initially received 5 mcg BID for 4 weeks. After 4 weeks, those patients either continued to receive exenatide 5 mcg BID or had their dose increased to 10 mcg BID.

Patients assigned to placebo received placebo BID throughout the study. A total of 1,446 patients were randomized in the three 30-week trials: 991 (69%) were White, 224 (16%) were Hispanic or Latino and 174 (12%) were of Black of African American ethnicity. Mean HbA 1c values at baseline for the trials ranged from 8.2% to 8.7%.

In the placebo-controlled trial of 16 weeks duration, exenatide (n=121) or placebo (n=112) was added to existing thiaz… [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 rats at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection. Benign thyroid C-cell adenomas were observed in female rats at all exenatide doses. The incidences in female rats were 8% and 5% in the two control groups and 14%, 11% and 23% in the low-, medium- and high-dose groups with systemic exposures of 5-, 22-, and 130-times, respectively, the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on plasma area under the curve (AUC).

In a 104-week carcinogenicity study in mice at doses of 18, 70, or 250 mcg/kg/day administered by bolus SC injection, no evidence of tumors was observed at doses up to 250 mcg/kg/day, a systemic exposure up to 95-times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC. Exenatide was not mutagenic or clastogenic, with or without metabolic activation, in the Ames bacterial mutagenicity assay or chromosomal aberration assay in Chinese hamster ovary cells. Exenatide was negative in the in vivo mouse micronucleus assay.

In mouse fertility studies with SC doses of 6, 68, or 760 mcg/kg/day, males were treated for 4 weeks prior to and throughout mating, and females were treated 2 weeks prior to mating and throughout mating until gestation day 7. No adverse effect on fertility was observed at 760 mcg/kg/day, a systemic exposure 390-times the human exposure resulting from the maximum recommended dose of 20 mcg/day, based on AUC.