Bydureon BCise

Exenatide.

Each autoinjector delivers a dose of 2 mg of exenatide in 0.85 mL.
Excipients/Inactive Ingredients: Powder: poly (D,L-lactide-co-glycolide), sucrose.
Vehicle: Medium chain triglycerides.

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues. ATC code: A10BJ01.
Pharmacology: Pharmacodynamics: Mechanism of action: Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that exhibits several antihyperglycaemic actions of glucagon-like peptide-1 (GLP-1). The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind to and activate the known human GLP-1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/or other intracellular signalling pathways.
Exenatide increases, on a glucose-dependent basis, the secretion of insulin from pancreatic beta cells. As blood glucose concentrations decrease, insulin secretion subsides. When exenatide was used in combination with metformin and/or a thiazolidinedione, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin and/or a thiazolidinedione which may be due to this glucose-dependent insulinotropic mechanism (see Precautions).
Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in patients with type 2 diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. However, exenatide does not impair the normal glucagon response and other hormone responses to hypoglycaemia.
Exenatide slows gastric emptying, thereby reducing the rate at which meal-derived glucose appears in the circulation.
Administration of exenatide has been shown to reduce food intake, due to decreased appetite and increased satiety.
Pharmacodynamic effects: Exenatide improves glycaemic control through the sustained effects of lowering both postprandial and fasting glucose concentrations in patients with type 2 diabetes. Unlike native GLP-1, prolonged-release exenatide has a pharmacokinetic and pharmacodynamic profile in humans suitable for once weekly administration.
A pharmacodynamic study with exenatide demonstrated in patients with type 2 diabetes (n = 13) a restoration of first phase insulin secretion and improved second phase insulin secretion in response to an intravenous bolus of glucose.
Clinical efficacy and safety: The results of two studies with Bydureon BCise and six long-term clinical studies of prolonged-release exenatide are presented as follows; these studies comprised 1766 subjects (556 treated with Bydureon BCise), 53 % men and 47 % women, 304 subjects (17 %) were ≥ 65 years of age.
In addition, a double-blind, placebo-controlled cardiovascular outcome study (EXSCEL) enrolled 14,752 subjects with type 2 diabetes and any level of CV risk when added to the current usual care.
Glycaemic control: Bydureon BCise: In a 28-week open-label study, Bydureon BCise was compared to immediate-release exenatide in subjects on a diet and exercise programme alone or with a stable regimen of oral glucose-lowering medicinal products. Both treatment groups had a reduction in HbA_1c compared to baseline. Bydureon BCise demonstrated superiority to immediate-release exenatide in reducing HbA_1c from baseline to Week 28 (Table 1). The 28-week comparator-controlled period of the study was followed by a 24-week extension period during which all participating subjects received treatment with this medicinal product. The effect on HbA_1c remained clinically significant over 52 weeks but partially diminished over time in the group that had initially received Bydureon BCise.
Both Bydureon BCise and immediate-release exenatide patients achieved a reduction in weight at Week 28 compared to baseline (Table 1). The difference between the two treatment groups was not significant. The reductions in body weight were sustained at Week 52. (See Table 1.)

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In a 28-week open-label study (oral medication-blinded), Bydureon BCise was compared to sitagliptin and placebo in subjects also using metformin ≥ 1,500 mg daily. Bydureon BCise demonstrated superiority to both sitagliptin and placebo in reducing HbA_1c from baseline to Week 28 (Table 2).
Both Bydureon BCise and sitagliptin patients achieved a reduction in weight at Week 28 compared to baseline (Table 2). The difference between the two treatment groups was not significant. (See Table 2.)

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Prolonged-release exenatide: In two studies prolonged-release exenatide 2 mg once weekly has been compared to immediate-release exenatide 5 mcg given twice daily for 4 weeks followed by immediate-release exenatide 10 mcg given twice daily. One study was of 24 weeks in duration (n = 252) and the other of 30 weeks (n = 295) followed by an open labelled extension where all patients were treated with prolonged-release exenatide 2 mg once weekly, for a further 7 years (n = 258). In both studies, decreases in HbA_1c were evident in both treatment groups as early as the first post-treatment HbA_1c measurement (Weeks 4 or 6).
Prolonged-release exenatide resulted in a statistically significant reduction in HbA_1c compared to patients receiving immediate-release exenatide (Table 3).
A clinically relevant effect of prolonged-release exenatide and immediate-release exenatide treated subjects was observed on HbA_1c, regardless of the background anti-diabetic therapy in both studies.
Clinically and statistically significantly more subjects on prolonged-release compared to immediate-release exenatide patients achieved an HbA_1c reduction of ≤ 7 % or < 7 % in the two studies (p < 0.05 and p ≤ 0.0001 respectively).
Both prolonged-release and immediate-release exenatide patients achieved a reduction in weight compared to baseline, although the difference between the two treatment arms was not significant.
In the uncontrolled study extension, evaluable patients who switched from immediate release to prolonged-release exenatide at week 30 (n = 121), achieved the same improvement in HbA_1c of -2.0 % at Week 52 compared to baseline as patients treated with prolonged-release exenatide. For all patients completing the uncontrolled study extension of 7 years (n = 122 of 258 patients included in the extension phase), HbA_1c gradually increased over time from week 52 onwards, but was still reduced compared to baseline after 7 years -1.5%). Weight loss was sustained over 7 years in these patients. (See Table 3.)

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A study of 26-week duration has been conducted, in which prolonged-release exenatide 2 mg is compared to insulin glargine once daily. Compared with insulin glargine treatment, prolonged-release exenatide demonstrated a superior change in HbA_1c, significantly lowered mean body weight and was associated with fewer hypoglycaemic events (Table 4). (See Table 4.)

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The 156-week results were consistent with those previously reported in the 26-week interim report. Treatment with prolonged-release exenatide persistently significantly improved glycaemic control and weight control, compared to the insulin glargine treatment. Safety findings at 156 weeks were consistent with those reported at 26 weeks.
In a 26-week double-blind study prolonged-release exenatide was compared to maximum daily doses of sitagliptin and pioglitazone in subjects also using metformin. All treatment groups had a significant reduction in HbA_1c compared to baseline. Prolonged-release exenatide demonstrated superiority to both sitagliptin and pioglitazone with respect to change in HbA_1c from baseline.
Prolonged-release exenatide demonstrated significantly greater weight reductions compared to sitagliptin. Patients on pioglitazone gained weight (Table 5). (See Table 5.)

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In a 28-week, double-blind study, the combination of prolonged-release exenatide and dapagliflozin was compared to prolonged-release exenatide alone and dapagliflozin alone in subjects also using metformin. All treatment groups had a reduction in HbA_1c compared to baseline. The prolonged-release exenatide and dapagliflozin treatment group showed superior reductions in HbA_1c from baseline compared to prolonged-release exenatide alone and dapagliflozin alone (Table 6).
The combination of prolonged-release exenatide and dapagliflozin demonstrated significantly greater weight reductions compared to either medicinal product alone (Table 6). (See Table 6.)

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In a 28-week double-blind study, prolonged-release exenatide added to insulin glargine alone or with metformin was compared to placebo added to insulin glargine alone or with metformin. Insulin glargine was dosed targeting a fasting plasma glucose of 4.0 to 5.5 mmol/L (72 to 99 mg/dL). Prolonged-release exenatide demonstrated superiority to placebo in reducing HbA_1c from baseline to Week 28 (Table 7).
Prolonged-release exenatide was superior to placebo in reducing body weight at Week 28 (Table 7). (See Table 7.)

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Cardiovascular evaluation: EXSCEL was a pragmatic cardiovascular (CV) outcome study in patients with type 2 diabetes and any level of CV risk. A total of 14,752 patients were randomized 1:1 to either prolonged-release exenatide 2mg once weekly or placebo, added to the current usual care which could include SGLT2 inhibitors. Patients were followed as in routine clinical practice for a median of 38.7 months with a median treatment duration of 27.8 months. The vital status was known at the end of the study for 98.9% and 98.8% of the patients in the prolonged-release exenatide and placebo group, respectively. The mean age at study entry was 62 years (with 8.5% of the patients ≥ 75 years). Approximately 62% of the patients were male. The mean BMI was 32.7 kg/m² and the mean duration of diabetes was 13.1 years. The mean HbA_1c was 8.1%. Approximately 49.3% had mild renal impairment (estimated glomerular filtration rate [eGFR] ≥ 60 to ≤ 89 mL/min/1.73 m²) and 21.6% had moderate renal impairment (eGFR ≥ 30 to ≤ 59 mL/min/1.73 m²). Overall, 26.9% of patients did not have any prior CV event, 73.1% had at least one prior CV event.
The primary safety (noninferiority) and efficacy (superiority) endpoint in EXSCEL was the time to first confirmed Major Adverse Cardiac Event (MACE): cardiovascular (CV)-related death, nonfatal myocardial infarction (MI) or nonfatal stroke. All-cause mortality was the initial secondary endpoint assessed.
Prolonged-release exenatide did not increase the cardiovascular risk in patients with type 2 diabetes mellitus compared to placebo when added to current usual care (HR:0.91; 95% CI: 0.832, 1.004; P<0.001 for non-inferiority) see Figure 1. In a pre-specified subgroup analysis in EXSCEL, the HR for MACE was 0.86 (95% CI: 0.77-0.97) in patients with baseline eGFR ≥ 60 mL/min/1.73 m² and 1.01 (95% CI: 0.86-1.19) in patients with baseline eGFR < 60 mL/min/1.73 m². The results of the primary composite and secondary cardiovascular endpoints are shown in Figure 2. (See Figures 1 and 2.)

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The need for additional antihyperglycaemic medication was reduced by 33% with the prolonged-release exenatide group (exposure-adjusted incidence of 10.5 per 100 pt-year) compared to the placebo group (exposure-adjusted incidence of 15.7 per 100 pt-year). A reduction in HbA_1c was observed over the course of the trial with an overall treatment difference of -0.53% (prolonged-release exenatide vs. placebo).
Body weight: A reduction in body weight compared to baseline has been observed in studies with prolonged-release exenatide formulations. This reduction in body weight was seen irrespective of the occurrence of nausea although the reduction was larger in the group with nausea (mean reduction of -1.9 kg to -5.2 kg with nausea versus -1.0 kg to -2.9 kg without nausea).
Plasma/serum glucose: Treatment with prolonged-release exenatide resulted in significant reductions in fasting plasma/serum glucose concentrations, these reductions were observed as early as 4 weeks. In the placebo-controlled study with insulin glargine, the change from baseline to Week 28 in fasting plasma glucose was -0.7 mmol/L for the prolonged-release exenatide group and -0.1 mmol/L for the placebo group. Additional reductions in postprandial concentrations were also observed.
For both prolonged-release exenatide formulations, the improvement in fasting plasma glucose concentrations was sustained through 52 weeks.
Beta-cell function: Clinical studies with prolonged-release exenatide formulations have indicated improved beta-cell function, using measures such as the homeostasis model assessments (HOMA-B). The effect on beta-cell function was sustained through 52 weeks.
Blood pressure: A reduction in systolic blood pressure was observed in the studies with prolonged-release exenatide formulations (0.8 mmHg to 4.7 mmHg). In the 30-week immediate-release exenatide comparator study both prolonged-release and immediate-release exenatide significantly reduced systolic blood pressure from baseline (4.7±1.1 mmHg and 3.4±1.1 mmHg respectively); the difference between the treatments was not significant. Improvements in blood pressure were maintained through 52 weeks.
In the placebo-controlled study with insulin glargine, the change from baseline to Week 28 in systolic blood pressure was -2.6 mmHg for the prolonged-release exenatide group and -0.7 mmHg for the placebo group.
Treatment with prolonged-release exenatide and dapagliflozin combination at Week 28 resulted in a significant mean change reduction of -4.3±0.8 mmHg in systolic blood pressure compared to prolonged-release exenatide alone of -1.2±0.8 mmHg (p<0.01) or to dapagliflozin alone of -1.8±0.8 mmHg (p<0.05).
Fasting lipids: The prolonged-release exenatide formulations have shown no negative effects on lipid parameters.
Paediatric population: The European Medicines Agency has deferred the obligation to submit the results of studies with prolonged-release exenatide formulations in one or more subsets of the paediatric population in type 2 diabetes mellitus (see Dosage & Administration for information on paediatric use).
Pharmacokinetics: The absorption properties of exenatide reflect the extended release properties of the prolonged-release exenatide formulation. Once absorbed into the circulation, exenatide is distributed and eliminated according to its known systemic pharmacokinetic properties (as described as follows).
Absorption: Following weekly administration of 2 mg Bydureon BCise, mean exenatide concentrations exceeded minimal efficacious concentrations (~ 50 pg/mL) in 2 weeks with gradual increase in the average plasma exenatide concentration up to Week 8. Subsequently, exenatide concentrations of approximately 153-208 pg/mL were maintained, indicating that steady state was achieved. Steady-state exenatide concentrations are maintained during the one-week interval between doses with minimal peak to trough fluctuation from this average therapeutic concentration.
Distribution: The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of exenatide is 28 L.
Biotransformation and elimination: Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation. The mean apparent clearance of exenatide is 9 L/h. These pharmacokinetic characteristics of exenatide are independent of the dose. Approximately 10 weeks after discontinuation of prolonged-release exenatide therapy, mean plasma exenatide concentrations fell below minimal detectable concentrations.
Special populations: Renal impairment: No clinically meaningful differences were observed in steady state exenatide concentrations or tolerability in patients with mild to moderate renal impairment (eGFR 30 to 89 mL/min/1.73m²) receiving Bydureon BCise, compared to those with normal renal function.
Hepatic insufficiency: No pharmacokinetic study has been performed in patients with hepatic insufficiency. Exenatide is cleared primarily by the kidney; therefore hepatic dysfunction is not expected to affect blood concentrations of exenatide.
Gender, race and body weight: Gender, race and body weight have no clinically relevant influence on exenatide pharmacokinetics.
Elderly: Data in elderly are limited, but suggest no marked changes in exenatide exposure with increased age up to about 75 years old.
In a pharmacokinetic study of immediate-release exenatide in patients with type 2 diabetes, administration of exenatide (10 mcg) resulted in a mean increase of exenatide AUC by 36 % in 15 elderly subjects aged 75 to 85 years compared to 15 subjects aged 45 to 65 years likely related to reduced renal function in the older age group (see Dosage & Administration).
Paediatric population: In a single-dose pharmacokinetic study of immediate-release exenatide in 13 patients with type 2 diabetes and between the ages of 12 and 16 years, administration of exenatide (5 mcg) resulted in slightly lower mean AUC (16 % lower) and C_max (25 % lower) compared to those observed in adults. No pharmacokinetics study of prolonged-release exenatide has been conducted in the paediatric population.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, or genotoxicity conducted with immediate-release exenatide or prolonged-release exenatide formulations.
Thyroid tumours have been observed in rats and mice with long acting GLP-1 receptor agonists. In a 2-year rat carcinogenicity study with prolonged-release exenatide, an increased incidence of C-cell adenomas and C-cell carcinomas was observed at doses ≥ 2-fold the human systemic exposure based on AUC. The clinical relevance of these findings is currently unknown.
Animal studies with exenatide did not indicate harmful effects with respect to fertility; high doses of exenatide caused skeletal effects and reduced foetal and neonatal growth.

Bydureon is indicated in adults 18 years and older with type 2 diabetes mellitus to improve glycaemic control in combination with other glucose-lowering medicinal products including basal insulin, when the therapy in use, together with diet and exercise, does not provide adequate glycaemic control.
For study results with respect to combinations, effects on glycaemic control and cardiovascular events, and the populations studies, see Precautions, Interactions and Pharmacology: Pharmacodynamics under Actions.

Posology: The recommended dose is 2 mg exenatide once weekly.
Patients switching from immediate-release exenatide (Byetta) to prolonged-release exenatide (Bydureon or Bydureon BCise) may experience transient elevations in blood glucose concentrations, which generally improve within the first four weeks after initiation of therapy. Patients switching between the prolonged-release exenatide products (Bydureon or Bydureon BCise) may do so, with no expected relevant effect on blood glucose concentrations.
When prolonged-release exenatide is added to existing metformin and/or thiazolidinedione therapy, the current dose of metformin and/or thiazolidinedione can be continued. When added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce the risk of hypoglycaemia (see Precautions).
Prolonged-release exenatide should be administered once a week on the same day each week. The day of weekly administration can be changed if necessary as long as the last dose was administered at least three days before. Prolonged-release exenatide can be administered at any time of day, with or without meals.
If a dose is missed, it should be administered as soon as practical, provided the next regularly scheduled dose is due in 3 days or more. Thereafter, patients can resume their usual once weekly dosing schedule.
If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, the patient should not administer the missed dose, but instead resume prolonged-release exenatide on the next regularly scheduled dosing day.
The use of this medicinal product does not require additional self-monitoring. Blood glucose self-monitoring is necessary to adjust the dose of sulphonylurea and of insulin, particularly when prolonged-release exenatide therapy is started and insulin is reduced. A stepwise approach to insulin dose reduction is recommended.
If a different glucose-lowering treatment is started after the discontinuation of prolonged-release exenatide, consideration should be given to the prolonged release of the product (see Pharmacology: Pharmacokinetics under Actions).
Special populations: Elderly: No dose adjustment is required based on age. However, as renal function generally declines with age, consideration should be given to the patient's renal function (see Renal impairment as follows) (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50 to 80 ml/min). Clinical experience in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min) is limited. Prolonged-release exenatide is not recommended in these patients.
Prolonged-release exenatide is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 ml/min) (see Precautions).
Hepatic impairment: No dose adjustment is necessary for patients with hepatic impairment (see Pharmacology: Pharmacokinetics under Actions).
Paediatric population: The safety and efficacy of prolonged-release exenatide in children and adolescents aged under 18 years have not yet been established. Currently available data are described in Pharmacology: Pharmacokinetics under Actions but no recommendation on a posology can be made.
Method of administration: Subcutaneous use.
Prolonged-release exenatide is for self-administration by the patient. Each autoinjector can only be used by one person and is for single use.
Prior to initiation of prolonged-release exenatide, it is strongly recommended that patients and caregivers be trained by their healthcare professional. The "Instructions for the User", provided in the carton, must be followed carefully.
Each dose should be administered in the abdomen, thigh, or the back of the upper arm as a subcutaneous injection immediately after the medicinal product is fully mixed.
When used with insulin, prolonged-release exenatide and insulin must be administered as two separate injections.
For instructions on the preparation of the medicinal product before administration, see Special precautions for disposal and other handling under Cautions for Usage and the "Instructions for the User".

Effects of overdoses with exenatide (based on immediate-release exenatide clinical studies) included severe nausea, severe vomiting and rapidly declining blood glucose concentrations. In the event of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms.

Hypersensitivity to the active substance or to any of the excipients listed in Description.

Prolonged-release exenatide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Prolonged-release exenatide is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependent patients after rapid discontinuation or dose reduction of insulin (see Dosage & Administration).
Prolonged-release exenatide must not be administered by intravenous or intramuscular injection.
Renal impairment: In patients with end stage renal disease receiving dialysis, single doses of immediate release exenatide increased frequency and severity of gastrointestinal adverse reactions; therefore, prolonged release exenatide formulations are not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 ml/min). The clinical experience in patients with moderate renal impairment is limited and the use of prolonged-release exenatide is not recommended.
There have been uncommon events of altered renal function with exenatide, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring haemodialysis. Some of these events occurred in patients experiencing events that may affect hydration, including nausea, vomiting, and/or diarrhoea and/or receiving medicinal products known to affect renal function/hydration status. Concomitant medicinal products included angiotensin converting enzymes inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinal products and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative medicinal products, including exenatide.
Severe gastrointestinal disease: Prolonged-release exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Its use is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting, and diarrhoea. Therefore, the use of this medicinal product is not recommended in patients with severe gastrointestinal disease.
Acute pancreatitis: Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. In clinical studies of Bydureon BCise, acute pancreatitis occurred in 0.4% of patients. There have been spontaneously reported events of acute pancreatitis with prolonged-release exenatide. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, the use of this medicinal product should be discontinued; if acute pancreatitis is confirmed, it should not be restarted. Caution should be exercised in patients with a history of pancreatitis.
Concomitant medicinal products: The concurrent use of prolonged-release exenatide formulations with D-phenylalanine derivatives (meglitinides), alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists has not been studied. The concurrent use of a formulation of prolonged-release and immediate-release exenatide has not been studied and is not recommended.
Interaction with warfarin: There have been spontaneously reported cases of increased INR (International Normalized Ratio), sometimes associated with bleeding, with concomitant use of warfarin and exenatide (see Interactions).
Hypoglycaemia: The risk of hypoglycaemia was increased when prolonged-release exenatide was used in combination with a sulphonylurea in clinical studies. Furthermore, in the clinical studies, patients on a sulphonylurea combination with mild renal impairment had an increased incidence of hypoglycaemia compared to patients with normal renal function. To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea should be considered.
Rapid weight loss: Rapid weight loss at a rate of > 1.5 kg per week has been reported in patients treated with exenatide. Weight loss of this rate may have harmful consequences. Patients with rapid weight loss should be monitored for signs and symptoms of cholelithiasis.
Discontinuation of treatment: After discontinuation, the effect of prolonged-release exenatide may continue as plasma levels of exenatide decline over 10 weeks. Choice of other medicinal products and dose selection should be considered accordingly, as adverse reactions may continue and efficacy may, at least partly, persist until exenatide levels decline.
Effects on ability to drive and use machines: Prolonged-release exenatide has minor influence on the ability to drive and use machines. When used in combination with a sulphonylurea, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines.

Women of childbearing potential: Due to the long washout period of prolonged-release exenatide, women of childbearing potential should use contraception during treatment with prolonged-release exenatide. This medicine should be discontinued at least 3 months before a planned pregnancy.
Pregnancy: There are no adequate data from the use of prolonged-release exenatide in pregnant women. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). The potential risk for humans is unknown. Prolonged-release exenatide should not be used during pregnancy and the use of insulin is recommended.
Breast-feeding: It is unknown whether exenatide is excreted in human milk. Prolonged-release exenatide should not be used during breast-feeding.
Fertility: No fertility studies in humans have been conducted.

Summary of the safety profile: The most frequent adverse reactions during the clinical studies were gastrointestinal-related (mainly nausea (8 %), which tended to dissipate with continued treatment), headache (4 %) and injection site reactions, such as injection site pruritus (3 %) and injection site erythema (2 %). In addition, hypoglycaemia with a sulphonylurea occurred very commonly (see Description of selected adverse reactions, as follows). Most adverse reactions were mild to moderate in intensity.
Tabulated list of adverse reactions: The frequency of adverse reactions of Bydureon BCise identified from clinical studies are summarised in Table 8 as follows.
The pooled clinical studies data set for Bydureon BCise comprises two phase 3 comparator-controlled studies of 6 to 12 months duration. The follow-up and extension phases of studies are included in the pool. Background therapies included diet and exercise alone or with metformin, a sulphonylurea, a thiazolidinedione or a combination of oral glucose-lowering medicinal products. Adverse reactions that have been observed with the prolonged-release exenatide but not in clinical studies with Bydureon BCise are also included in Table 8.
Background therapies in the prolonged-release exenatide clinical trials included diet and exercise, metformin, a sulphonylurea, a thiazolidinedione, a combination of oral glucose-lowering agents or a basal insulin.
The reactions are listed as follows as MedDRA preferred term by system organ class and absolute frequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000) very rare (< 1/10,000) and not known (cannot be estimated from the available data). (See Table 8.)

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Description of selected adverse reactions: Drug-induced thrombocytopenia: Drug-induced thrombocytopenia (DITP) with exenatide-dependent anti-platelet antibodies has been reported in the postmarketing setting. DITP is an immune-mediated reaction that is caused by drug-dependent platelet-reactive antibodies. These antibodies cause destruction of platelets in the presence of the sensitizing drug.
Hypoglycaemia: There were no events of major hypoglycaemia with Bydureon BCise. The overall incidence of minor hypoglycaemia was 6.3 %. This incidence was increased when it was used in combination with a sulphonylurea (26.1 %) compared to no sulphonylurea (0.9 %) (see Precautions). To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea may be considered (see Dosage & Administration and Precautions).
When prolonged-release exenatide was added to basal insulin, no initial dose adjustment of insulin was required. Prolonged-release exenatide in combination with basal insulin showed no clinically significant differences in the incidence of hypoglycaemic episodes compared to insulin. There were no episodes of major hypoglycaemia in the prolonged-release exenatide with insulin group.
Nausea: The most frequently reported gastrointestinal adverse reaction was nausea. During the controlled period of the clinical study comparing Bydureon BCise with immediate-release exenatide, nausea was reported in 9.6 % and 20.5 % of patients in each group. Overall, 9.3 % of patients treated with Bydureon BCise reported nausea during the controlled period of both clinical studies. Most episodes of nausea were mild to moderate, associated with the initiation of treatment and decreased over time.
Injection site reactions: During the controlled period of the clinical studies, injection site reactions were observed more frequently in patients treated with Bydureon BCise versus comparator-treated patients (24 % versus 4 % with immediate-release exenatide). These injection site reactions were generally mild and usually did not lead to discontinuation of study medication. Patients may be treated to relieve symptoms, while continuing treatment. Subsequent injections should use a different site of injection each week. In postmarketing experience with prolonged-release exenatide, cases with injection site abscesses and cellulitis have been reported.
Subcutaneous injection site nodules were observed frequently in clinical studies, consistent with the known properties of poly (D,L-lactide co-glycolide) polymer microsphere formulations. Most individual nodules did not interfere with study participation and resolved over time.
Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop antibodies to exenatide following treatment with prolonged-release exenatide.
Approximately 42 % of patients developed low titre antibodies to exenatide and 32 % of patients developed high titre antibodies at any time during the studies. The percentage of these subjects with positive antibody titres, in particular high titres, peaked at approximately weeks 8 to 16 of dosing and then diminished over time. At the study endpoint, approximately 43 % of patients had low titre antibodies to exenatide and 14 % of patients had high titre antibodies. Overall, the level of glycaemic control (HbA_1c) in patients treated with Bydureon BCise with low titre antibodies at the last visit (-1.1 % to -1.5 %) was comparable to that observed in those without antibody titres (-1.1 % to -1.4 %). While patients with high titre antibodies at the last visit had an attenuated HbA_1c response, HbA_1c reductions in these patients were clinically relevant (-0.6 % to -0.7 %).
Amongst patients treated with Bydureon BCise evaluable for antibodies (N = 393), the incidence of potentially immunogenic injection site reactions (most commonly injection site nodule) during the two studies was approximately 20 %. These reactions were less commonly observed in antibody-negative patients (16 %) and patients with low titre antibodies (16 %) compared with those with high titre antibodies (27 %).
Rapid weight loss: In a 30-week study, approximately 3 % (n = 4/148) of prolonged-release exenatide treated patients experienced at least one-time period of rapid weight loss (recorded body weight loss between two consecutive study visits of greater than 1.5 kg/week).
Increased heart rate: A mean increase in heart rate (HR) of 2.4 beats per minute (bpm) from baseline (74 bpm) was observed in the controlled period of the Bydureon BCise clinical studies. Fifteen percent of prolonged-release exenatide treated patients had mean increases in HR of ≥10 bpm; approximately 5 % to 10 % of subjects within the other treatment groups had mean increases in HR of ≥10 bpm.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to AstraZeneca.

Sulphonylureas: The dose of a sulphonylurea may require adjustment due to the increased risk of hypoglycaemia associated with sulphonylurea therapy (see Dosage & Administration and Precautions).
Gastric emptying: The results of a study using paracetamol as a marker of gastric emptying suggest that the effect of prolonged-release exenatide to slow gastric emptying is minor and not expected to cause clinically significant reductions in the rate and extent of absorption of concomitantly administered oral medicinal products. Therefore, no dose adjustments for medicinal products sensitive to delayed gastric emptying are required.
When 1,000 mg paracetamol tablets were administered, either with or without a meal, following 14 weeks of prolonged-release exenatide therapy, no significant changes in paracetamol AUC were observed compared to the control period. Paracetamol C_max decreased by 16 % (fasting) and 5 % (fed) and t_max was increased from approximately 1 hour in the control period to 1.4 hours (fasting) and 1.3 hours (fed).
The following interaction studies have been conducted using 10 mcg immediate-release exenatide but not prolonged-release exenatide formulations: Warfarin: A delay in t_max of about 2 h was observed when warfarin was administered 35 min after immediate-release exenatide. No clinically relevant effects on C_max or AUC were observed. Increased INR has been spontaneously reported during concomitant use of warfarin and prolonged-release exenatide. INR should be monitored during initiation of prolonged-release exenatide therapy in patients on warfarin and/or cumarol derivatives (see Precautions and Adverse Reactions).
Hydroxy methyl glutaryl coenzyme A reductase inhibitors: Lovastatin AUC and C_max were decreased approximately 40 % and 28 %, respectively, and t_max was delayed about 4 h when immediate-release exenatide was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In 30-week placebo-controlled clinical studies with immediate-release exenatide, concomitant use of exenatide and HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles (see Pharmacology: Pharmacodynamics under Actions). No predetermined dose adjustment is required; however, lipid profiles should be monitored as appropriate.
Digoxin and lisinopril: In interaction studies of the effect of immediate-release exenatide on digoxin and lisinopril there were no clinical relevant effects on C_max or AUC, however, a delay in t_max of about 2 h was observed.
Ethinyl estradiol and levonorgestrel: Administration of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) one hour before immediate-release exenatide did not alter the AUC, C_max or C_min of either ethinyl estradiol or levonorgestrel. Administration of the oral contraceptive 35 minutes after exenatide did not affect AUC but resulted in a reduction of the C_max of ethinyl estradiol by 45 %, and C_max of levonorgestrel by 27-41 %, and a delay in t_max by 2-4 h due to delayed gastric emptying. The reduction in C_max is of limited clinical relevance and no adjustment of dosing of oral contraceptives is required.
Paediatric population: Interaction studies with exenatide have only been performed in adults.

Special precautions for disposal and other handling: Autoinjector is for single-use only.
Patients and caregivers should be trained by their healthcare professional.
The BCise autoinjector must be removed from the refrigerator and rested flat for at least 15 minutes prior to injection. The suspension must be mixed by shaking hard for at least 15 seconds. The suspension should be visually inspected prior to use. The suspension should only be used if it is evenly mixed, white to off-white and cloudy, with no white medicine seen along the side, bottom or top of the window. After the suspension is fully mixed, the preparation steps must be completed immediately and the suspension injected subcutaneously. Please see the package leaflet and "Instructions for the User" for additional information on suspension and administration.
The patient should be instructed to discard the autoinjector safely after each injection.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.

Store in a refrigerator (2°C - 8°C).
The autoinjector may be kept for up to 4 weeks below 30°C prior to use.
Store in the original package in order to protect from light.
The autoinjector must be stored flat.

Antidiabetic Agents

A10BJ01 - exenatide ; Belongs to the class of glucagon-like peptide-1 (GLP-1) analogues. Used in the treatment of diabetes.

P₁S₁S₃