Common Adverse Reactions

Tables 1 and 2 summarize adverse reactions with an incidence ≥5% reported in the six comparator-controlled 24- to 30-week trials of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione, or combination of these oral antidiabetic agents.

Nausea was a common adverse reaction associated with initiation of treatment with BYDUREON and usually decreased over time.

Adverse Reactions Leading to Study Withdrawal

The incidence of withdrawal due to adverse reactions was 4.1% (N=57) for BYDUREON-treated patients, 4.9% (N=13) for BYETTA-treated patients, and 2.9% (N=46) for other comparator-treated patients in the six comparator-controlled 24- to 30-week trials. The most common classes of adverse reactions (0.5%) leading to withdrawal for BYDUREON-treated patients were, Gastrointestinal Disorders 1.6% (N=22) versus 4.1% (N=11) for BYETTA and 1.9% (N=30) for other comparators, and Administration Site Conditions 0.8% (N=11) versus 0.0% for BYETTA and 0.2% (N=3) for other comparators. The most frequent adverse reactions within each of these respective classes were, nausea 0.4% (N=6) for BYDUREON versus 1.5% (N=4) for BYETTA and 0.8% (N=12) for other comparators, and injection-site nodule, 0.4% (N=6) for BYDUREON versus 0.0% for BYETTA and 0.0% for other comparators.

Hypoglycemia

Table 3 summarizes the incidence of minor hypoglycemia in the six comparator-controlled 24- to 30-week trials of BYDUREON used as monotherapy or as add-on to metformin, a sulfonylurea, a thiazolidinedione, or combination of these oral antidiabetic agents. In these trials, an event was classified as minor hypoglycemia if there were symptoms of hypoglycemia with a concomitant glucose <54 mg/dL and the patient was able to self-treat.

Injection-Site Adverse Reactions

In five comparator-controlled 24- to 30-week trials, injection-site reactions were observed more frequently in patients treated with BYDUREON (17.1%) than in patients treated with BYETTA (12.7%), titrated insulin glargine (1.8%), or those patients who received placebo injections (sitagliptin (10.6%), pioglitazone (6.4%), and metformin (13.0%) treatment groups). These reactions for patients treated with BYDUREON were more commonly observed in antibody-positive patients (14.2%) compared with antibody-negative patients (3.1%), with a greater incidence in those with higher titer antibodies [see Warnings and Precautions (5.7)]. Incidence of injection-site reactions for patients treated with BYETTA was similar for antibody-positive patients (5.8%) and antibody-negative patients (7.0%). One percent of patients treated with BYDUREON withdrew due to injection-site adverse reactions (injection-site mass, injection-site nodule, injection-site pruritus, and injection-site reaction).

Subcutaneous injection-site nodules may occur with the use of BYDUREON. In a separate 15-week study in which information on nodules were collected and analyzed, 24 out of 31 subjects (77%) experienced at least 1 injection-site nodule during treatment; 2 subjects (6.5%) reported accompanying localized symptoms. The mean duration of events was 27 days. The formation of subcutaneous nodules is consistent with the known properties of the microspheres used in BYDUREON.

Increase in Heart Rate

Increases in heart rate from baseline ranging from 1.5 to 4.5 beats per minute have been observed in comparator-controlled clinical trials.

Other Adverse Reactions

The following adverse reactions were also reported in three 30-week controlled trials of BYETTA (N=963) add-on to metformin and/or sulfonylurea, with an incidence of ≥1% and reported more frequently than with placebo: feeling jittery (9% BYETTA, 4% placebo), dizziness (9% BYETTA, 6% placebo), asthenia (4% BYETTA, 2% placebo), and hyperhidrosis (3% BYETTA, 1% placebo).

Risk Summary

Limited data with exenatide, the active ingredient in BYDUREON, in pregnant women are not sufficient to determine a drug-associated risk for major birth defects or miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Based on animal reproduction studies, there may be risks to the fetus from exposure to BYDUREON during pregnancy. BYDUREON should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Animal reproduction studies identified increased adverse fetal and neonatal outcomes from exposure to exenatide extended-release during pregnancy, or from exposure to exenatide, during pregnancy and lactation, in association with maternal effects. In rats, exenatide extended-release administered during the period of organogenesis reduced fetal growth and produced skeletal ossification deficits at doses that approximate clinical exposures at the maximum recommended human dose (MRHD) of 2 mg/week. In mice, exenatide administered during gestation and lactation caused increased neonatal deaths at doses that approximate clinical exposures at the MRHD (see Data). Based on animal data, advise pregnant women of the potential risk to a fetus.

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with an HbA1c >7 and has been reported to be as high as 20-25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryofetal risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Animal Data

Pregnant rats given subcutaneous doses of 0.3, 1, or 3 mg/kg exenatide extended-release every 3 days during organogenesis had systemic exposures 3-, 7-, and 17-times human exposure, respectively, at the maximum recommended human dose (MRHD) of 2 mg/week BYDUREON based on plasma exenatide exposure (AUC) comparison. Reduced fetal growth at all doses and skeletal ossification deficits at 1 and 3 mg/kg occurred at doses that decreased maternal food intake and body weight gain.

In studies evaluating reproduction and development in pregnant mice and rabbits, maternal animals were administered exenatide, the active ingredient in BYDUREON, by subcutaneous injection twice a day. Differences in embryo-fetal developmental toxicity from subcutaneously injected exenatide extended-release and exenatide were not evaluated in mice, rats, or rabbits.

In pregnant mice given 6, 68, 460, or 760 mcg/kg/day exenatide during fetal organogenesis, skeletal variations associated with slowed fetal growth, including changes in number of rib pairs or vertebral ossifications sites, and wavy ribs were observed at 760 mcg/kg/day, a dose that produced maternal toxicity and yielded systemic exposure 200 times the human exposure resulting from the MRHD of BYDUREON based on AUC comparison.

In pregnant rabbits given 0.2, 2, 22, 156, or 260 mcg/kg/day exenatide during fetal organogenesis, irregular fetal skeletal ossifications were observed at 2 mcg/kg/day, a dose yielding systemic exposure up to 4 times the human exposure from the MRHD of BYDUREON based on AUC comparison.

In maternal mice given 6, 68, or 760 mcg/kg/day exenatide from gestation day 6 through lactation day 20 (weaning), an increased number of neonatal deaths were observed on postpartum days 2 to 4 in dams given 6 mcg/kg/day, a dose yielding a systemic exposure equivalent to the human exposure from the MRHD of BYDUREON based on AUC comparison.

Glucose-Dependent Insulin Secretion

The effect of exenatide infusion on glucose-dependent insulin secretion rates (ISR) was investigated in 11 healthy subjects. In these healthy subjects, on average, the ISR response was glucose-dependent (Figure 1). Exenatide did not impair the normal glucagon response to hypoglycemia.

Figure 1: Mean (SE) Insulin Secretion Rates During Infusion of Exenatide or Placebo by Treatment, Time, and Glycemic Condition in Healthy Subjects

SE = standard error.
Notes: 5 mmol = 90 mg/dL, 4 mmol/L = 72 mg/dL, 3.2 mmol/L = 58 mg/dL; Study medication infusion was started at time = 0 minutes.
Statistical assessments were for the last 30 minutes of each glycemic step, during which the target glucose concentrations were maintained.
*p <0.05, exenatide treatment relative to placebo.

Glucagon Secretion

In patients with type 2 diabetes, exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycemia.

Gastric Emptying

Exenatide slows gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

Fasting and Postprandial Glucose

In a clinical study in adults with type 2 diabetes mellitus, treatment with once weekly BYDUREON resulted in mean reductions in fasting plasma glucose of -45 mg/dL and 2-hour PPG concentrations of -95 mg/dL.

Cardiac Electrophysiology

The effect of exenatide at therapeutic (253 pg/mL) and supratherapeutic (627 pg/mL) concentrations, following an intravenous infusion on QTc interval was evaluated in a randomized, placebo- and active-controlled (moxifloxacin 400 mg) three-period crossover thorough QT study in 74 healthy subjects. The upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on population correction method (QTcP) was below 10 ms. Therefore, exenatide was not associated with prolongation of the QTc interval at therapeutic and supratherapeutic concentrations.

Absorption

Following a single dose of BYDUREON, exenatide is released from the microspheres over approximately 10 weeks. There is an initial period of release of surface-bound exenatide followed by a gradual release of exenatide from the microspheres, which results in two subsequent peaks of exenatide in plasma at around Week 2 and Week 6 to 7, respectively, representing the hydration and erosion of the microspheres.

Following initiation of once every 7 days (weekly) administration of 2 mg BYDUREON, a gradual increase in the plasma exenatide concentration is observed over 6 to 7 weeks. After 6 to 7 weeks, mean exenatide concentrations of approximately 300 pg/mL were maintained over once every 7 days (weekly) dosing intervals indicating that steady state was achieved.

Distribution

The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of BYETTA is 28.3 L and is expected to remain unchanged for BYDUREON.

Metabolism

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 9.1 L/hour and is independent of the dose. Approximately 10 weeks after discontinuation of BYDUREON therapy, plasma exenatide concentrations generally fall below the minimal detectable concentration of 10 pg/mL.

Drug Interaction Studies

Specific Populations

Monotherapy

BYDUREON Monotherapy versus Metformin, Sitagliptin, and Pioglitazone

A 26-week, randomized, comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to metformin, sitagliptin, and pioglitazone in patients with type 2 diabetes whose glycemic control was inadequate with diet and exercise (NCT00676338).

A total of 820 patients were studied: 552 (67%) were Caucasian, 102 (12%) were East Asian, 71 (9%) were West Asian, 65 (8%) were Hispanic, 25 (3.0%) were Black, 4 (0.5%) were Native American, and 1 was classified otherwise. The mean baseline HbA1c was 8.5%. Patients were randomly assigned to receive BYDUREON 2 mg once every seven days (weekly), titrated metformin from 1000 to 2500 mg/day, sitagliptin 100 mg/day or titrated pioglitazone from 30 to 45 mg/day, all dosed according to approved labeling.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation). Treatment with BYDUREON 2 mg once weekly (QW) resulted in mean HbA1c reduction that was statistically significantly greater compared to sitagliptin 100 mg/day. The mean reduction in HbA1c was non-inferior compared with metformin 1000-2500 mg/day (mean dose 2077 mg/day at study endpoint). Non-inferiority of BYDUREON 2 mg QW to pioglitazone 30-45 mg/day (mean dose 40 mg/day at study endpoint) in reducing HbA1c after 26 weeks of treatment was not demonstrated (the mean change from baseline in HbA1c after 26 weeks was -1.6% with BYDUREON and -1.7% with pioglitazone). The non-inferiority margin was set at +0.3% in this study. The results for the primary endpoint at 26 weeks are summarized in Table 5.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 56%, 52%, 40%, and 55% for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively. Patients who did achieve and HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were -41 mg/dL, -36 mg/dL, -20 mg/dL, and -46 mg/dL, and for body weight were -2.0 kg, -2.0 kg, -0.8 kg, and +1.5 kg for BYDUREON, metformin, sitagliptin, and pioglitazone, respectively.

Combination Therapy

BYDUREON versus Sitagliptin and Pioglitazone, All as Add-on to Metformin Therapy

A 26-week double-blind comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to sitagliptin and pioglitazone in patients with type 2 diabetes whose glycemic control was inadequate with metformin therapy (NCT00637273).

A total of 491 patients were studied 168 (34.2%) were Caucasian, 143 (29.1%) were Hispanic, 119 (24.2%) were Asian, 52 (10.6%) were Black, 3 (0.6%) were Native American, and 6 (1.2%) were classified otherwise. The mean baseline HbA1c was 8.5%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly), sitagliptin 100 mg/day or pioglitazone 45 mg/day, in addition to their existing metformin therapy.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation). In this study, treatment with BYDUREON 2 mg QW resulted in a statistically significant mean HbA1c reduction compared to sitagliptin 100 mg/day. There was a numerically greater reduction in HbA1c with BYDUREON compared to pioglitazone, but there was not sufficient evidence to conclude superiority of BYDUREON 2 mg QW to pioglitazone 45 mg/day in reducing HbA1c after 26 weeks of treatment. Results for the primary endpoint at 26 weeks are summarized in Table 6.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 46%, 30%, and 39% for BYDUREON, sitagliptin, and pioglitazone, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were ‑32 mg/dL, ‑16 mg/dL and ‑27 mg/dL, and for body weight were ‑2.3 kg, ‑0.8 kg and +2.8 kg for BYDUREON, sitagliptin, and pioglitazone, respectively.

BYDUREON versus Insulin Glargine, Both as Add-on to Metformin or Metformin + Sulfonylurea Therapy

A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to titrated insulin glargine in patients with type 2 diabetes whose glycemic control was inadequate with metformin or metformin plus sulfonylurea therapy (NCT00641056).

A total of 456 patients were studied: 379 (83.1%) were Caucasian, 47 (10.3%) were Hispanic, 25 (5.5%) were East Asian, 3 (0.7%) were Black, and 2 (0.4%) were West Asian. Background therapy was either metformin (70%) or metformin plus sulfonylurea (30%). The mean baseline HbA1c was 8.3%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly) or insulin glargine once daily in addition to their existing oral antidiabetic therapy. Insulin glargine was dosed to a target fasting glucose concentration of 72 to 100 mg/dL. The mean dose of insulin glargine was 10 units/day at baseline and 31 units/day at endpoint. At Week 26, 21% of insulin glargine treated patients were at fasting glucose goal.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation). Treatment with BYDUREON once weekly resulted in a mean reduction in HbA1c from baseline at 26 weeks of -1.5%. The mean reduction in HbA1c seen in insulin glargine arm at 26 weeks was ‑1.3%. The difference in observed effect size between BYDUREON and glargine in this trial excluded the pre-specified non-inferiority margin of +0.3%.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 57% and 48% for BYDUREON and insulin glargine, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose in this study were ‑38 mg/dL and ‑50 mg/dL, and for body weight were ‑2.6 kg and +1.4 kg for BYDUREON and insulin glargine, respectively.

BYDUREON versus BYETTA, Both as Monotherapy or as Add-on to Metformin, a Sulfonylurea, a Thiazolidinedione, or Combination of Oral Agents

A 24-week, randomized, open-label trial was conducted to compare the safety and efficacy of BYDUREON to BYETTA in patients with type 2 diabetes and inadequate glycemic control with diet and exercise alone or with oral antidiabetic therapy, including metformin, a sulfonylurea, a thiazolidinedione, or combination of two of those therapies (NCT00877890).

A total of 252 patients were studied: 149 (59%) were Caucasian, 78 (31%) Hispanic, 15 (6%) Black, and 10 (4%) Asian. Patients were treated with diet and exercise alone (19%), a single oral antidiabetic agent (47%), or combination therapy of oral antidiabetic agents (35%). The mean baseline HbA1c was 8.4%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly) or BYETTA (10 mcg twice daily), in addition to existing oral antidiabetic agents. Patients assigned to BYETTA initiated treatment with 5 mcg twice daily then increased the dose to 10 mcg twice daily after 4 weeks.

The primary endpoint was change in HbA1c from baseline to Week 24 (or the last value at time of early discontinuation). Treatment with BYDUREON 2 mg QW resulted in a statistically significantly greater mean HbA1c reduction compared to BYETTA 10 mcg twice daily. Change in body weight was a secondary endpoint. Twenty-four-week study results are summarized in Table 7.

Reductions from mean baseline (97/94 kg) in body weight were observed in both BYDUREON (−2.3 kg) and BYETTA (−1.4 kg) treatment groups.

BYDUREON versus Liraglutide, Both as Add-on to Metformin, a Sulfonylurea, Metformin + Sulfonylurea, or Metformin + Pioglitazone Therapy

A 26-week open-label comparator-controlled trial was conducted to compare the safety and efficacy of BYDUREON to liraglutide in patients with type 2 diabetes whose glycemic control was inadequate with metformin, a sulfonylurea, metformin plus sulfonylurea, or metformin plus pioglitazone therapy (NCT01029886).

A total of 911 patients were studied: 753 (82.7%) were Caucasian, 111 (12.2%) were Asian, 32 (3.5%) were American Indian or Alaska Native, 8 (0.9%) were Black, 6 (0.7%) were multiple races, and 1 (0.1%) was Pacific Islander. Background therapy was either a single oral antidiabetic agent (35%) or a combination of oral antidiabetic agents (65%). The mean baseline HbA1c was 8.4%. Patients were randomly assigned to receive BYDUREON 2 mg once every 7 days (weekly) or liraglutide uptitrated from 0.6 mg/day to 1.2 mg/day, then 1.8 mg/day in addition to their existing oral antidiabetic therapy. Each titration was to be completed after at least one week, but could be delayed if the patient had severe nausea or vomiting as established by the investigator. Patients not tolerating the 1.8 mg/day dose of liraglutide by Week 4 were discontinued from the study.

The primary endpoint was change in HbA1c from baseline to Week 26 (or the last value at time of early discontinuation). Treatment with BYDUREON once weekly resulted in a mean reduction in HbA1c from baseline at 26 weeks of -1.3%. The mean reduction in HbA1c seen in the liraglutide arm at 26 weeks was ‑1.5%. The HbA1c reduction with BYDUREON did not meet predefined non-inferiority criteria compared to liraglutide 1.8 mg/day. The non-inferiority margin was set at +0.25% in this study. Results for the primary endpoint at 26 weeks are summarized in Table 8.

The proportion of patients with a Week 26 value achieving HbA1c of less than 7% at Week 26 were 48% and 56% for BYDUREON and liraglutide, respectively. Patients who did achieve an HbA1c goal <7% and discontinued before Week 26 were not included as responders. The mean changes from baseline to Week 26 for fasting serum glucose were ‑32 mg/dL and ‑38 mg/dL, and for body weight were ‑2.7 kg and ‑3.6 kg for BYDUREON and liraglutide, respectively.

BYDUREON in Combination with Dapagliflozin versus BYDUREON Alone and Dapagliflozin Alone, All as Add-On to Metformin

A 28‑week double‑blind comparator‑controlled trial was conducted to compare the efficacy of BYDUREON and dapagliflozin (an SGLT2 inhibitor) to BYDUREON alone and dapagliflozin alone in patients with type 2 diabetes with inadequate glycemic control with metformin therapy (NCT02229396).

A total of 694 patients were studied; 580 (83.6%) were Caucasian, 96 (13.8%) were Black, 5 (0.7%) were Asian, 2 (0.3%) were American Indian or Alaska Native and 11 (1.6%) were classified otherwise. The mean baseline HbA1c was 9.3%. All patients entered a 1‑week placebo lead–in period. Patients with HbA1c ≥8.0% and ≤12% and on metformin at a dose of at least 1,500 mg per day were randomly assigned to receive either BYDUREON 2 mg once every 7 days (weekly) plus dapagliflozin 10 mg once daily, BYDUREON 2 mg once weekly, or dapagliflozin 10 mg once daily.

The primary endpoint was change in HbA1c from baseline to Week 28. At Week 28, BYDUREON in combination with dapagliflozin provided statistically significantly greater reductions in HbA1c (‑1.77%) compared to BYDUREON alone (‑1.42%, p=0.012) and dapagliflozin alone (‑1.32%, p=0.001). BYDUREON in combination with dapagliflozin provided statistically significantly greater reductions in FPG (‑57.35 mg/dL) compared to BYDUREON alone (‑40.53, p <0.001) and dapagliflozin alone (‑44.72 mg/dL, p=0.006).

BYDUREON versus Placebo, Both as Add-On to Basal Insulin or Basal Insulin + Metformin Therapy

A 28‑week, double‑blind, placebo‑controlled trial was conducted to compare the safety and efficacy of BYDUREON to placebo when added to basal insulin glargine, with or without metformin, in patients with type 2 diabetes with inadequate glycemic control (NCT02229383).

A total of 460 patients were studied: 400 (87.0%) were White, 47 (10.2%) were Black or African American, 6 (1.3%) were Asian, 1 (0.2%) was American Indian or Alaska Native, 1 (0.2%) was Pacific Islander and 5 (1.1%) were classified otherwise. Patients on sulfonylurea therapy discontinued sulfonylurea. Patients on metformin continued on the same dose of metformin. All patients initially entered an 8‑week insulin dose‑titration phase. Insulin glargine was to be titrated every 3 days with an aim of achieving a target fasting plasma glucose concentration of 72 to 99 mg/dL. Following the titration period, patients with HbA1c ≥7.0% and ≤10.5% were then randomly assigned to receive either BYDUREON 2 mg once every 7 days (weekly) or placebo once every 7 days (weekly).

The primary endpoint was the change in HbA1c from baseline to Week 28. Compared to placebo, treatment with BYDUREON resulted in a statistically significant reduction in mean HbA1c from baseline to Week 28 (Table 9).

Analyses include measurements post rescue therapy and post premature discontinuation of study medication.

The mean change in fasting plasma glucose from baseline to Week 28 was -12.50 mg/dL for BYDUREON and -2.26 mg/dL for placebo. The mean change from baseline to Week 28 in body weight was -0.92 kg for BYDUREON and +0.38 kg for placebo.