Bydureon

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ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS



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1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 2 mg of exenatide.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

Powder: white to off-white powder.
Solvent: clear, colourless to pale yellow to pale brown solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 studied, see sections 4.4, 4.5, and 5.1.

4.2 Posology and method of administration

Posology
The recommended dose is 2 mg exenatide once weekly. 

Patients switching from immediate-release (Byetta) to prolonged-release (Bydureon or Bydureon 
BCise) exenatide, may experience transient elevations in blood glucose concentrations, which 
generally improve within the first two 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 section 4.4).

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. 



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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 prolonged-release exenatide 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 medicinal product (see section 
5.2).

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) (see section 5.2).

Renal impairment
No dose adjustment is necessary for patients with mild or moderate renal impairment.

Prolonged-release exenatide is not recommended for use in patients with end-stage renal disease or 
severe renal impairment (glomerular filtration rate [GFR] < 30 mL/min) (see section 4.4).

Hepatic impairment
No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

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 section 5.2 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 kit should be used by one 
person only 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 suspension of the powder in the solvent. 

When used with insulin, prolonged-release exenatide and insulin must be administered as two separate 
injections.

For instructions on the suspension of the medicinal product before administration, see section 6.6 and 
the “Instructions for the User”.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.



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4.4 Special warnings and precautions for use

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 section 4.2). 

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 is not recommended for use in patients with end-stage renal disease or severe renal 
impairment (GFR < 30 mL/min).

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 prolonged-release exenatide 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 prolonged-release exenatide, acute pancreatitis occurred in 0.3% 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, prolonged-release exenatide should be discontinued; if acute pancreatitis is confirmed, 
prolonged-release exenatide 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 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 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 Normalised Ratio), 
sometimes associated with bleeding, with concomitant use of warfarin and exenatide (see section 4.5).

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.



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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.

Excipients
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. 
essentially “sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

Sulphonylureas
The dose of a sulphonylurea may require adjustment due to the increased risk of hypoglycaemia 
associated with sulphonylurea therapy (see sections 4.2 and 4.4). 

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 Cmax decreased by 16% (fasting) and 5% (fed) 
and tmax 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:

Warfarin
A delay in tmax of about 2 h was observed when warfarin was administered 35 min after 
immediate-release exenatide. No clinically relevant effects on Cmax 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 sections 4.4 and 4.8).

Hydroxy methyl glutaryl coenzyme A reductase inhibitors
Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and tmax 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 
section 5.1). 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 Cmax or AUC, however, a delay in tmax of about 2 h was observed. 



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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, Cmax or Cmin 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 Cmax of ethinyl estradiol by 45%, and 
Cmax of levonorgestrel by 27-41%, and a delay in tmax by 2-4 h due to delayed gastric emptying. The 
reduction in Cmax 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.

4.6 Fertility, pregnancy and lactation

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 medicinal product 
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 section 5.3). 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.

4.7 Effects on ability to drive and use machines

Prolonged-release exenatide has minor influence on the ability to drive and use machines. When
prolonged-release exenatide is used in combination with a sulphonylurea, patients should be advised to 
take precautions to avoid hypoglycaemia while driving and using machines.

4.8 Undesirable effects

Summary of the safety profile
The most frequent adverse reactions were mainly gastrointestinal related (nausea which was the most 
frequent reaction and associated with the initiation of treatment and decreased over time, and 
diarrhoea). In addition, injection site reactions (pruritus, nodules, erythema), hypoglycaemia (with a 
sulphonylurea), and headache occurred. Most adverse reactions associated with prolonged-release 
exenatide were mild to moderate in intensity.

Tabulated list of adverse reactions
The frequency of adverse reactions of prolonged-release exenatide identified from clinical studies and 
spontaneous reports (not observed in clinical studies, frequency not known) are summarised in Table 1 
below.

In the prolonged-release exenatide clinical studies, background therapies included diet and exercise, 
metformin, a sulphonylurea, a thiazolidinedione, a combination of oral glucose-lowering medicinal 
products or a basal insulin. 



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The reactions are listed below 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).

Table 1: Adverse reactions of prolonged-release exenatide identified from clinical studies and 
spontaneous reports

System organ class 
/adverse reaction 
terms

Frequency of occurrence

Very 
common

Common Uncommon Rare Very rare Not 
known

Blood and lymphatic system disorders
Drug-induced 
thrombocytopenia

X4

Immune system disorders
Anaphylactic reaction X1

Metabolism and nutrition disorders
Hypoglycaemia (with 
a sulphonylurea)

X1

Hypoglycaemia (with 
insulin)

X2,3

Decreased appetite X1

Dehydration X1

Nervous system disorders
Headache X1

Dizziness X1

Dysgeusia X1

Somnolence X1

Gastrointestinal disorders
Intestinal obstruction X1

Acute pancreatitis (see 
section 4.4)

X1

Nausea X1

Vomiting X1

Diarrhoea X1

Dyspepsia X1

Abdominal pain X1

Gastroesophageal 
reflux disease

X1

Abdominal distension X1

Eructation X1

Constipation X1

Flatulence X1

Skin and subcutaneous tissue disorders
Macular and papular 
rash

X4

Pruritus, and/ or 
urticaria

X1

Angioneurotic oedema X4

Injection site abscesses 
and cellulitis

X4



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System organ class 
/adverse reaction 
terms

Frequency of occurrence

Very 
common

Common Uncommon Rare Very rare Not 
known

Hyperhidrosis X1

Alopecia X1

Renal and urinary disorders
Altered renal function, 
including acute renal 
failure, worsened 
chronic renal failure, 
renal impairment, 
increased serum 
creatinine (see section 
4.4).

X1

General disorders and administration site conditions
Injection site pruritus X1

Fatigue X1

Injection site erythema X1

Injection site rash X1

Asthenia X1

Feeling jittery X1

Investigations
International 
normalised ratio 
increased (see section 
4.4)

X4

1 Rate based on twelve prolonged-release exenatide completed long-term efficacy and safety studies 
n = 2868 total (patients on sulphonylurea n = 1002).
2 Based on hypoglycaemic events that 1. Result in loss of consciousness, seizure, or coma which 
resolves after administration of glucagon or glucose OR 2. Require third-party assistance to resolve 
because of impairment in consciousness or behaviour and has glucose value of < 54 mg/dL 
(3 mmol/L) OR 3. Result in symptoms consistent with hypoglycaemia with a concomitant glucose 
< 54 mg/dL (3 mmol/L) prior to treatment.
3 Frequency reported from the 28-week controlled treatment period of the prolonged-release exenatide 
as add-on to insulin glargine study (N=231).
4 Rate based on prolonged-release exenatide spontaneous reports data (unknown denominator).

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
The incidence of hypoglycaemia was increased when prolonged-release exenatide was used in 
combination with a sulphonylurea (24.0% versus 5.4%) (see section 4.4). To reduce the risk of 
hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea may 
be considered (see sections 4.2 and 4.4).



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Prolonged-release exenatide was associated with a significantly lower incidence of episodes of 
hypoglycaemia than basal insulin in patients also receiving metformin therapy (3% versus 19%) and in 
patients also receiving metformin plus sulphonylurea therapy (20% versus 42%).

Across 12 studies of prolonged-release exenatide most episodes (99.9% n = 649) of hypoglycaemia 
were minor, and resolved with oral administration of carbohydrate. One patient was reported with 
major hypoglycaemia since he had a low blood glucose value (2.2 mmol/L) and requested assistance 
with oral carbohydrate treatment which resolved the event.

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 adverse reaction was nausea. In patients treated with prolonged-release 
exenatide, generally 20% reported at least one episode of nausea compared to 34% of 
immediate-release exenatide patients. Most episodes of nausea were mild to moderate. With continued 
therapy, the frequency decreased in most patients who initially experienced nausea. 

The incidence of withdrawal due to adverse events during the 30-week controlled study was 6% for 
prolonged-release exenatide treated patients, 5% for immediate-release exenatide treated patients. The 
most common adverse events leading to withdrawal in either treatment group were nausea and 
vomiting. Withdrawal due to nausea or vomiting each occurred in < 1% for prolonged-release 
exenatide treated patients and 1% for immediate-release exenatide treated patients. 

Injection site reactions
Injection site reactions were observed more frequently in prolonged-release exenatide treated patients 
versus comparator-treated patients (16% versus range of 2-7%) during the 6-month controlled phase of 
studies. These injection site reactions were generally mild and usually did not lead to withdrawal from 
studies. Patients may be treated to relieve symptoms, while continuing treatment. Subsequent 
injections should use a different site of injection each week. In postmarketing experiences, cases with 
injection site abscesses and cellulitis have been reported. 

Small subcutaneous injection site nodules were observed very frequently in clinical studies, consistent 
with the known properties of poly (D,L-lactide co-glycolide) polymer microsphere formulations. Most 
individual nodules were asymptomatic, did not interfere with study participation and resolved over 4 
to 8 weeks.

Immunogenicity
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, 
patients may develop antibodies to exenatide following treatment with prolonged-release exenatide. In 
most patients who develop antibodies, antibody titres diminish over time. 

The presence of antibodies (high or low titres) is not predictive of glycaemic control for an individual 
patient.

In clinical studies of prolonged-release exenatide, approximately 45% of patients had low titre 
antibodies to exenatide at study endpoint. Overall, the percentage of antibody positive patients was 
consistent across clinical studies. Overall, the level of glycaemic control (HbA1c) was comparable to 
that observed in those without antibody titres. On average in the phase 3 studies, 12% of the patients 
had higher titre antibodies. In a proportion of these the glycaemic response to prolonged-release 
exenatide was absent at the end of the controlled period of studies; 2.6% of patients showed no 
glucose improvement with higher titre antibodies whereas 1.6% showed no improvement while 
antibody negative.



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Patients who developed antibodies to exenatide tend to have more injection site reactions (for 
example: redness of skin and itching), but otherwise similar rates and types of adverse events as those 
with no antibodies to exenatide.

For prolonged-release exenatide treated patients, the incidence of potentially immunogenic injection 
site reactions (most commonly pruritus with or without erythema) during the 30-week and the two 
26-week studies was 9%. These reactions were less commonly observed in antibody-negative patients 
(4%) compared with antibody-positive patients (13%), with a greater incidence in those with higher 
titre antibodies.

Examination of antibody-positive specimens revealed no significant cross-reactivity with similar 
endogenous peptides (glucagon or GLP-1).

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 2.6 beats per minute (bpm) from baseline (74 bpm) was 
observed in pooled prolonged-release exenatide 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 via the national reporting system 
listed in Appendix V.

4.9 Overdose

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. 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATC 
code: A10BJ01.

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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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thiazolidinedione which may be due to this glucose-dependent insulinotropic mechanism (see section 
4.4).

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 long-term clinical studies of prolonged-release exenatide are presented below; these 
studies comprised 1356 subjects treated with prolonged-release exenatide, 52% men and 48% women; 
230 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
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 HbA1c were 
evident in both treatment groups as early as the first post-treatment HbA1c measurement (Weeks 4 or 
6).

Prolonged-release exenatide resulted in a statistically significant reduction in HbA1c compared to 
patients receiving immediate-release exenatide (Table 2).

A clinically relevant effect of prolonged-release exenatide and immediate-release exenatide treated 
subjects was observed on HbA1c, 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 HbA1c 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 HbA1c of -2.0% 
at Week 52 compared to baseline as patients treated with prolonged-release exenatide.



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For all patients completing the uncontrolled study extension of 7 years (n = 122 of 258 patients 
included in the extension phase), HbA1c 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.

Table 2: Results of two studies of prolonged-release versus immediate-release exenatide in 
combination with diet and exercise alone, metformin and/or sulphonylurea and metformin 
and/or thiazolidinedione (intent to treat patients)

24-Week Study Prolonged-
release 
exenatide 2 mg 

Immediate-
release 
exenatide 
10 mcg twice 
daily

N 129 123
Mean HbA1c (%)
Baseline 8.5 8.4
Change from baseline (± SE) -1.6 (±0.1)** -0.9 (±0.1)
Mean difference change from baseline between 
treatments (95% CI)

-0.67 (-0.94, -0.39)**

Patients (%) achieving HbA1c < 7% 58 30
Change in fasting plasma glucose (mmol/L) (± SE) -1.4 (±0.2) -0.3 (±0.2)
Mean body weight (kg)
Baseline 97 94
Change from baseline (± SE) -2.3 (±0.4) -1.4 (± 0.4)
Mean difference change from baseline between 
treatments (95% CI)

-0.95 (-1.91, 0.01)

30-Week Study

N 148 147
Mean HbA1c (%)
Baseline 8.3 8.3
Change from baseline (± SE) -1.9 (±0.1)* -1.5 (±0.1)
Mean difference change from baseline between 
treatments (95% CI)

-0.33 (-0.54, -0.12)*

Patients (%) achieving HbA1c ≤ 7% 73 57
Change in fasting plasma glucose (mmol/L) (± SE) -2.3 (±0.2) -1.4 (±0.2)
Mean body weight (kg)
Baseline 102 102
Change from baseline (± SE) -3.7 (±0.5) -3.6 (±0.5)
Mean difference change from baseline between 
treatments (95% CI)

-0.08 (-1.29, 1.12)

SE = standard error, CI = confidence interval, * p < 0.05, **p < 0.0001

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 HbA1c, significantly lowered mean body weight and was 
associated with fewer hypoglycaemic events (Table 3).



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Table 3: Results of one 26-week study of prolonged-release exenatide versus insulin glargine in 
combination with metformin alone or metformin and sulphonylurea (intent to treat patients)

Prolonged-
release 
exenatide
2 mg 

Insulin 

glargine
1

N 233 223
Mean HbA1c (%)
Baseline 8.3 8.3
Change from baseline (± SE) -1.5 (± 0.1)* -1.3 (± 0.1)*
Mean difference change from baseline between 
treatments (95% CI)

-0.16 (-0.29, -0.03)*

Patients (%) achieving HbA1c ≤ 7% 62 54
Change in fasting serum glucose (mmol/L) (± SE) -2.1 (± 0.2) -2.8 (± 0.2)
Mean body weight (kg)
Baseline 91 91
Change from baseline (± SE) -2.6 (± 0.2) +1.4 (±0.2)
Mean difference change from baseline between 
treatments (95% CI)

-4.05 (-4.57, -3.52)*

SE = standard error, CI = confidence interval, * p < 0.05
1
Insulin glargine was dosed to a target glucose concentration of 4.0 to 5.5 mmol/L (72 to 100 mg/dL).

The mean dose of insulin glargine at the beginning of treatment was 10.1 IU/day rising to 31.1 IU/day 
for insulin glargine-treated patients.

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 HbA1c compared to baseline. Prolonged-release exenatide demonstrated superiority to 
both sitagliptin and pioglitazone with respect to change in HbA1c from baseline. 

Prolonged-release exenatide demonstrated significantly greater weight reductions compared to 
sitagliptin. Patients on pioglitazone gained weight (Table 4).

Table 4: Results of one 26-week study of prolonged-release exenatide versus sitagliptin and 
versus pioglitazone in combination with metformin (intent to treat patients)



14

Prolonged-
release 
exenatide
2 mg

Sitagliptin 
100 mg

Pioglitazone 
45 mg

N 160 166 165
Mean HbA1c (%)
Baseline 8.6 8.5 8.5
Change from baseline (± SE) -1.6 (± 0.1)* -0.9 (± 0.1)* -1.2 (± 0.1)*
Mean difference change from baseline 
between treatments (95% CI) versus 
sitagliptin

-0.63 (-0.89, -0.37)**

Mean difference change from baseline 
between treatments (95% CI) versus 
pioglitazone

-0.32 (-0.57, -0.06)*

Patients (%) achieving HbA1c ≤ 7% 62 36 49
Change in fasting serum glucose 
(mmol/L) (± SE)

-1.8 (± 0.2) -0.9 (± 0.2) -1.5 (± 0.2)

Mean body weight (kg)
Baseline 89 87 88
Change from baseline (± SE) -2.3 (± 0.3) -0.8 (± 0.3) +2.8 (± 0.3)
Mean difference change from baseline 
between treatments (95% CI) versus 
sitagliptin

-1.54 (-2.35, -0.72)*

Mean difference change from baseline 
between treatments (95% CI) versus 
pioglitazone

-5.10 (-5.91, -4.28)**

SE = standard error, CI = confidence interval, *p < 0.05, **p < 0.0001

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 HbA1c compared to baseline. The 
prolonged-release exenatide and dapagliflozin treatment group showed superior reductions in HbA1c 
from baseline compared to prolonged-release exenatide alone and dapagliflozin alone (Table 5). 

The combination of prolonged-release exenatide and dapagliflozin demonstrated significantly greater 
weight reductions compared to either medicinal product alone (Table 5).

Table 5: Results of one 28-week study of prolonged-release exenatide and dapagliflozin versus 
prolonged-release exenatide alone and dapagliflozin alone, in combination with metformin 
(intent to treat patients)

Prolonged-release 
exenatide 2 mg QW

+

Dapagliflozin 10 mg 
QD

Prolonged-release 
exenatide 2 mg 

QW

+

Placebo QD

Dapagliflozin 
10 mg QD

+

Placebo QW

N 228 227 230

Mean HbA1c (%)

Baseline 9.3 9.3 9.3

Change from baseline (±SE)a -2.0 (±0.1) -1.6 (±0.1) -1.4 (±0.1)

Mean difference in change 
from baseline between 
combination and single 

-0.38*

(-0.63, -0.13)

-0.59**

(-0.84, -0.34)



15

Prolonged-release 
exenatide 2 mg QW

+

Dapagliflozin 10 mg 
QD

Prolonged-release 
exenatide 2 mg 

QW

+

Placebo QD

Dapagliflozin 
10 mg QD

+

Placebo QW

active medicinal product (95 
% CI)

Patients (%) achieving 
HbA1c 7%

45 27 19

Mean change from baseline 
in fasting plasma glucose 
(mmol/L) (±SE)a

-3.7 (±0.2) -2.5 (±0.2) -2.7 (±0.2)

Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-1.12**

(-1.55, -0.68)

-0.92**

(-1.36, -0.49)

Mean change from baseline 
in 2-hour postprandial 
plasma glucose (mmol/L) 
(SE) a

-4.9 (±0.2) -3.3 (±0.2) -3.4 (±0.2)

Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-1.54**

(-2.10, -0.98)

-1.49**

(-2.04, -0.93)

Mean body weight (kg)

Baseline 92 89 91

Change from baseline (±SE)a -3.6 (±0.3) -1.6 (±0.3) -2.2 (±0.3)

Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-2.00**

(-2.79, -1.20)

-1.33**

(-2.12, -0.55)

QW=once weekly, QD=once daily, SE = standard error, CI= confidence interval, N=number of 
patients.

a Adjusted least squares means (LS Means) and treatment group difference(s) in the change from 
baseline values at Week 28 are modelled using a mixed model with repeated measures (MMRM) 
including treatment, region, baseline HbA1c stratum (< 9.0% or ≥ 9.0%), week, and treatment by 
week interaction as fixed factors, and baseline value as a covariate.
*p < 0.01, **p < 0.001.
p-values are all adjusted p-values for multiplicity.
Analyses exclude measurements post rescue therapy and post premature discontinuation of study 
medicinal product.

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). 



16

Prolonged-release exenatide demonstrated superiority to placebo in reducing HbA1c from baseline to 
Week 28 (Table 6).

Prolonged-release exenatide was superior to placebo in reducing body weight at Week 28 (Table 6).

Table 6: Results of one 28-week study of prolonged-release exenatide versus placebo in 
combination with insulin glargine alone or with metformin (intent to treat patients)

Prolonged-release 
exenatide 2 mg 

+ Insulin glarginea

Placebo

+ Insulin glarginea

N 230 228

Mean HbA1c (%)

Baseline 8.5 8.5

Change from baseline (± SE)b -1.0 (±0.1) -0.2 (±0.1)

Mean difference in change from baseline 
between treatments (95% CI)

-0.74*

(-0.94, -0.54)

Patients (%) achieving HbA1c ≤ 7%c 33* 7

Mean body weight (kg)

Baseline 94 94

Change from baseline (± SE)b -1.0 (±0.3) 0.5 (±0.3)

Mean difference in change from baseline 
between treatments (95% CI)

-1.52*

(-2.19, -0.85)

Change from baseline in 2-hour postprandial 
plasma glucose (mmol/L) (± SE)b,d

-1.6 (±0.3) -0.1 (±0.3)

Mean difference in change from baseline 
between treatments (95% CI)

-1.54*

(-2.17, -0.91)

N=number of patients in each treatment group, SE = standard error, CI= confidence interval, *p-value 
< 0.001 (adjusted for multiplicity).
a. The LS means change in mean daily insulin dose was 1.6 units for the prolonged-release exenatide 
group and 3.5 units for the placebo group.
b. Adjusted LS means and treatment group difference(s) in the change from baseline values at Week 28 
are modeled using a mixed model with repeated measures (MMRM) including treatment, region, 
baseline HbA1c stratum (< 9.0% or ≥ 9.0%), baseline SU-use stratum (yes vs. no), week, and treatment 
by week interaction as fixed factors, and baseline value as a covariate. The absolute change in 2-hour 
postprandial plasma glucose at Week 28 is modeled similarly using ANCOVA.
c. All patients with missing endpoint data are imputed as non-responders.
d. After a standard meal tolerance test.
Analyses exclude measurements post rescue therapy and post premature discontinuation of study 
medicinal product.

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 randomised 1:1 to either prolonged-release exenatide
2 mg 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 



17

patients were male. The mean BMI was 32.7 kg/m2 and the mean duration of diabetes was 13.1 years. 
The mean HbA1c 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.

Figure 1: Time to First Adjudicated MACE (intent to treat patients) 

HR=hazard ratio, CI=confidence interval

Figure 2: Forest Plot: Analysis of Primary and Secondary Endpoints (intent to treat patients)

         Exenatide
         Placebo

Exenatide vs Placebo:
HR (95% CI)                 0.91 (0.832, 1.004)

Number at Risk
Months from Randomization

P
at

ie
nt

s 
w

it
h 

an
 E

ve
nt

 (
%

)

Exenatide

Placebo

MACE

All-cause death

CV-related death

Myocardial Infarction

Stroke

Hospitalisation for ACS

Hospitalisation for HF

Hazard Ratio    Exenatide Placebo

n (%)                    Event Rate      n (%)                     Event Rate   HR (95% CI)1

       <-Exenatide favored-     -Placebo favored->

)



18

ACS=acute coronary syndrome; CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazard 
ratio; MACE=major adverse cardiac event; MI=myocardial infarction; n=number of patients with an event; 
N=number of patients in treatment group.

1 HR (active/placebo) and CI are based on Cox proportional hazards regression model, stratified by prior CV 
event, with treatment group only as explanatory variable.

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 HbA1c 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 all prolonged-release exenatide 
studies. In the 4 comparator-controlled studies, this reduction in body weight was seen in patients 
treated with prolonged-release exenatide irrespective of the occurrence of nausea although the 
reduction was larger in the group with nausea (mean reduction of -2.9 kg to -5.2 kg with nausea 
versus -2.2 kg to -2.9 kg without nausea). 

In the 4 comparator-controlled studies, the proportion of patients who had both a reduction in weight 
and HbA1c ranged from 70 to 79% (the proportion of patients who had a reduction of HbA1c ranged 
from 88 to 96%). 

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. The improvement in fasting 
plasma glucose concentrations was durable through 52 weeks.

Beta-cell function
Clinical studies with prolonged-release exenatide have indicated improved beta-cell function, using 
measures such as the homeostasis model assessments (HOMA-B). The durability of effect on beta-cell 
function was maintained through 52 weeks.

Blood pressure
A reduction in systolic blood pressure was observed in the 4 comparator-controlled prolonged-release 
exenatide studies (2.9 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 base line (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
Prolonged-release exenatide has shown no negative effects on lipid parameters. 



19

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
prolonged-release exenatide in one or more subsets of the paediatric population in type 2 diabetes 
mellitus (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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 in this section).

Absorption
Following weekly administration of 2 mg prolonged-release exenatide, mean exenatide concentrations 
exceeded minimal efficacious concentrations (~ 50 pg/mL) in 2 weeks with gradual increase in the 
average plasma exenatide concentration over 6 to 7 weeks. Subsequently, exenatide concentrations of 
approximately 151-265 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
Population pharmacokinetic analysis of renal impaired patients receiving 2 mg prolonged-release 
exenatide indicate that there may be an increase in systemic exposure of approximately 74% and 23% 
(median prediction in each group) in moderate (N = 10) and mild (N = 56) renal impaired patients, 
respectively as compared to normal (N = 84) renal function patients. 

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 section 4.2).

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 



20

slightly lower mean AUC (16% lower) and Cmax (25% lower) compared to those observed in adults. 
No pharmacokinetics study of prolonged-release exenatide has been conducted in the paediatric 
population.

5.3 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. 

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder
poly (D,L-lactide-co-glycolide)
sucrose

Solvent
carmellose sodium 
sodium chloride
polysorbate 20
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal 
products.

6.3 Shelf life

3 years

After suspension
The suspension must be injected immediately after mixing the powder and the solvent. 

6.4 Special precautions for storage

Store in a refrigerator (2 ºC - 8 ºC).
Do not freeze.

The kit may be kept for up to 4 weeks below 30 ºC prior to use.
Store in the original package in order to protect from light.



21

For storage conditions after mixing of the medicinal product, see section 6.3.

6.5 Nature and contents of container

The powder is packaged in a 3 mL Type I glass vial sealed with a chlorobutyl rubber stopper and an 
aluminium seal with a plastic flip-off cap.

The solvent is packaged in a 1.5 mL Type 1 glass pre-filled syringe sealed with a bromobutyl rubber 
cap and a rubber plunger.

Each single-dose kit contains one vial of 2 mg exenatide, one pre-filled syringe of 0.65 mL solvent, 
one vial connector, and two injection needles (one spare).

Pack size of 4 single-dose kits and a multipack consisting of 12 (3 packs of 4) single-dose kits. Not all 
pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

The patient should be instructed to discard the syringe safely, with the needle still attached after each 
injection. The patient does not need to save any part of the single-use kit.

The solvent should be visually inspected prior to use. The solvent should only be used if it is clear and 
free of particulate matter. After suspension, the mixture should only be used if it is white to off white 
and cloudy.

Prolonged-release exenatide must be injected immediately after suspension of the powder in the 
solvent.

Prolonged-release exenatide that has been frozen must not be used.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/001-002

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 June 2011
Date of latest renewal: 18 February 2016

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu

http://www.ema.europa.eu/


22

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled pen contains 2 mg of exenatide. After suspension, each pen delivers a dose of 2 mg in 
0.65 mL.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for prolonged-release suspension for injection.

Powder: white to off-white powder.
Solvent: clear, colourless to pale yellow to pale brown solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 studied, see sections 4.4, 4.5, and 5.1.

4.2 Posology and method of administration

Posology
The recommended dose is 2 mg exenatide once weekly. 

Patients switching from immediate-release (Byetta) to prolonged-release (Bydureon or Bydureon 
BCise) exenatide may experience transient elevations in blood glucose concentrations, which 
generally improve within the first two 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 section 4.4).

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. 



23

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 prolonged-release exenatide 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 section 5.2).

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) (see section 5.2).

Renal impairment
No dose adjustment is necessary for patients with mild or moderate renal impairment.

Prolonged-release exenatide is not recommended for use in patients with end-stage renal disease or 
severe renal impairment (glomerular filtration rate [GFR] < 30mL/min) (see section 4.4).

Hepatic impairment
No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

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 section 5.2 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 pen 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 suspension of the powder in the solvent. 

When used with insulin, prolonged-release exenatide and insulin must be administered as two separate 
injections.

For instructions on the suspension of the medicinal product before administration, see section 6.6 and 
the “Instructions for the User”. 

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Prolonged-release exenatide should not be used in patients with type 1 diabetes mellitus or for the 
treatment of diabetic ketoacidosis.



24

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 section 4.2). 

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 is not recommended for use in patients with end-stage renal disease or severe renal 
impairment (GFR < 30mL/min). 

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 prolonged-release exenatide 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 prolonged-release exenatide, acute pancreatitis occurred in 0.3% 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, prolonged-release exenatide should be discontinued; if acute pancreatitis is confirmed, 
prolonged-release exenatide 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 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 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 section 4.5).

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



25

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.

Excipients
Sodium content: This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. 
essentially “sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

Sulphonylureas
The dose of a sulphonylurea may require adjustment due to the increased risk of hypoglycaemia 
associated with sulphonylurea therapy (see sections 4.2 and 4.4). 

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 Cmax decreased by 16% (fasting) and 5% (fed) 
and tmax 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:

Warfarin
A delay in tmax of about 2 h was observed when warfarin was administered 35 min after 
immediate-release exenatide. No clinically relevant effects on Cmax 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 sections 4.4 and 4.8).

Hydroxy methyl glutaryl coenzyme A reductase inhibitors
Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and tmax 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 
section 5.1). 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 Cmax or AUC, however, a delay in tmax of about 2 h was observed.



26

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, Cmax or Cmin 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 Cmax of ethinyl estradiol by 45%, and 
Cmax of levonorgestrel by 27-41%, and a delay in tmax by 2-4 h due to delayed gastric emptying. The 
reduction in Cmax 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.

4.6 Fertility, pregnancy and lactation

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 medicinal product 
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 section 5.3). 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.

4.7 Effects on ability to drive and use machines

Prolonged-release exenatide has minor influence on the ability to drive and use machines. When
prolonged-release exenatide is used in combination with a sulphonylurea, patients should be advised to 
take precautions to avoid hypoglycaemia while driving and using machines. 

4.8 Undesirable effects

Summary of the safety profile
The most frequent adverse reactions were mainly gastrointestinal related (nausea which was the most 
frequent reaction and associated with the initiation of treatment and decreased over time, and 
diarrhoea). In addition, injection site reactions (pruritus, nodules, erythema), hypoglycaemia (with a 
sulphonylurea), and headache occurred. Most adverse reactions associated with prolonged-release 
exenatide were mild to moderate in intensity.

Tabulated list of adverse reactions
The frequency of adverse reactions of prolonged-release exenatide identified from clinical studies and 
spontaneous reports (not observed in clinical studies, frequency not known) are summarised in Table 1 
below. 

In the prolonged-release exenatide clinical studies, background therapies included diet and exercise, 
metformin, a sulphonylurea, a thiazolidinedione, a combination of oral glucose-lowering medicinal 
products or a basal insulin. 



27

The reactions are listed below 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 < 1/1000), very rare (< 1/10,000) and not 
known (cannot be estimated from the available data).

Table 1: Adverse reactions of prolonged-release exenatide identified from clinical studies and 
spontaneous reports

System organ class 
/adverse reaction 
terms

Frequency of occurrence

Very 
common

Common Uncommon Rare Very rare Not 
known

Blood and lymphatic system disorders
Drug-induced 
thrombocytopenia

X4

Immune system disorders
Anaphylactic reaction X1

Metabolism and nutrition disorders
Hypoglycaemia (with 
a sulphonylurea)

X1

Hypoglycaemia (with 
insulin)

X2,3

Decreased appetite X1

Dehydration X1

Nervous system disorders
Headache X1

Dizziness X1

Dysgeusia X1

Somnolence X1

Gastrointestinal disorders
Intestinal obstruction X1

Acute pancreatitis (see 
section 4.4)

X1

Nausea X1

Vomiting X1

Diarrhoea X1

Dyspepsia X1

Abdominal pain X1

Gastroesophageal 
reflux disease

X1

Abdominal distension X1

Eructation X1

Constipation X1

Flatulence X1

Skin and subcutaneous tissue disorders
Macular and papular 
rash

X4

Pruritus, and/ or 
urticaria

X1

Angioneurotic oedema X4

Injection site abscesses 
and cellulitis

X4

Hyperhidrosis X1



28

System organ class 
/adverse reaction 
terms

Frequency of occurrence

Very 
common

Common Uncommon Rare Very rare Not 
known

Alopecia X1

Renal and urinary disorders
Altered renal function, 
including acute renal 
failure, worsened 
chronic renal failure, 
renal impairment, 
increased serum 
creatinine (see section 
4.4).

X1

General disorders and administration site conditions
Injection site pruritus X1

Fatigue X1

Injection site erythema X1

Injection site rash X1

Asthenia X1

Feeling jittery X1

Investigations
International 
normalised ratio 
increased (see section 
4.4)

X4

1 Rate based on twelve prolonged-release exenatide completed long-term efficacy and safety studies 
n=2868 total (patients on sulphonylurea n=1002).
2 Based on hypoglycaemic events that 1. Result in loss of consciousness, seizure, or coma which 
resolves after administration of glucagon or glucose OR 2. Require third-party assistance to resolve 
because of impairment in consciousness or behaviour and has glucose value of < 54 mg/dL 
(3 mmol/L) OR 3. Result in symptoms consistent with hypoglycaemia with a concomitant glucose 
< 54 mg/dL (3 mmol/L) prior to treatment.
3 Frequency reported from the 28-week controlled treatment period of the prolonged-release exenatide 
as add-on to insulin glargine study (N=231).
4 Rate based on prolonged-release exenatide spontaneous reports data (unknown denominator).

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
The incidence of hypoglycaemia was increased when prolonged-release exenatide was used in 
combination with a sulphonylurea (24.0% versus 5.4%) (see section 4.4). To reduce the risk of 
hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea may 
be considered (see sections 4.2 and 4.4).

Prolonged-release exenatide was associated with a significantly lower incidence of episodes of 
hypoglycaemia than basal insulin in patients also receiving metformin therapy (3% versus 19%) and in 
patients also receiving metformin plus sulphonylurea therapy (20% versus 42%).



29

Across 12 studies of prolonged-release exenatide most episodes (99.9% n = 649) of hypoglycaemia 
were minor, and resolved with oral administration of carbohydrate. One patient was reported with 
major hypoglycaemia since he had a low blood glucose value (2.2 mmol/L) and requested assistance 
with oral carbohydrate treatment which resolved the event.

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 adverse reaction was nausea. In patients treated with prolonged-release 
exenatide, generally 20% reported at least one episode of nausea compared to 34% of 
immediate-release exenatide patients. Most episodes of nausea were mild to moderate. With continued 
therapy, the frequency decreased in most patients who initially experienced nausea.

The incidence of withdrawal due to adverse events during the 30-week controlled study was 6% for 
prolonged-release exenatide treated patients, 5% for immediate-release exenatide treated patients. The 
most common adverse events leading to withdrawal in either treatment group were nausea and 
vomiting. Withdrawal due to nausea or vomiting each occurred in < 1% for prolonged-release 
exenatide treated patients and 1% for immediate-release exenatide treated patients.

Injection site reactions
Injection site reactions were observed more frequently in prolonged-release exenatide treated patients 
versus comparator-treated patients (16% versus range of 2-7%) during the 6-month controlled phase of 
studies. These injection site reactions were generally mild and usually did not lead to withdrawal from 
studies. Patients may be treated to relieve symptoms, while continuing treatment. Subsequent 
injections should use a different site of injection each week. In postmarketing experiences, cases with 
injection site abscesses and cellulitis have been reported.

Small subcutaneous injection site nodules were observed very frequently in clinical studies, consistent 
with the known properties of poly (D,L-lactide co-glycolide) polymer microsphere formulations. Most 
individual nodules were asymptomatic, did not interfere with study participation and resolved over 4 
to 8 weeks.

Immunogenicity
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, 
patients may develop antibodies to exenatide following treatment with prolonged-release exenatide. In 
most patients who develop antibodies, antibody titres diminish over time. 

The presence of antibodies (high or low titres) is not predictive of glycaemic control for an individual 
patient.

In clinical studies of prolonged-release exenatide, approximately 45% of patients had low titre 
antibodies to exenatide at study endpoint. Overall the percentage of antibody positive patients was 
consistent across clinical studies. Overall, the level of glycaemic control (HbA1c) was comparable to 
that observed in those without antibody titres. On average in the phase 3 studies, 12% of the patients 
had higher titre antibodies. In a proportion of these the glycaemic response to prolonged-release 
exenatide was absent at the end of the controlled period of studies; 2.6% of patients showed no 
glucose improvement with higher titre antibodies whereas 1.6% showed no improvement while 
antibody negative.

Patients who developed antibodies to exenatide tend to have more injection site reactions (for 
example: redness of skin and itching), but otherwise similar rates and types of adverse events as those 
with no antibodies to exenatide.



30

For prolonged-release exenatide treated patients, the incidence of potentially immunogenic injection 
site reactions (most commonly pruritus with or without erythema) during the 30-week and the two 
26-week studies was 9%. These reactions were less commonly observed in antibody-negative patients 
(4%) compared with antibody-positive patients (13%), with a greater incidence in those with higher
titre antibodies.

Examination of antibody-positive specimens revealed no significant cross-reactivity with similar 
endogenous peptides (glucagon or GLP-1).

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 2.6 beats per minute (bpm) from baseline (74 bpm) was 
observed in pooled prolonged-release exenatide 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 via the national reporting system 
listed in Appendix V.

4.9 Overdose

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. 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATC 
code: A10BJ01.

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 section 
4.4).

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. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


31

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 long-term clinical studies of prolonged-release exenatide are presented below; these 
studies comprised 1356 subjects treated with prolonged-release exenatide, 52% men and 48% women, 
230 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
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 HbA1c were 
evident in both treatment groups as early as the first post-treatment HbA1c measurement (Weeks 4 or 
6).

Prolonged-release exenatide resulted in a statistically significant reduction in HbA1c compared to 
patients receiving immediate-release exenatide (Table 2).

A clinically relevant effect of prolonged-release exenatide and immediate-release exenatide treated 
subjects was observed on HbA1c, 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 HbA1c 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 HbA1c 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), HbA1c 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.



32

Table 2: Results of two studies of prolonged-release versus immediate-release exenatide in 
combination with diet and exercise alone, metformin and/or sulphonylurea and metformin 
and/or thiazolidinedione (intent to treat patients)

24-Week Study Prolonged-
release 
exenatide 2 mg

Immediate-
release
exenatide 
10 mcg twice 
daily

N 129 123
Mean HbA1c (%)
Baseline 8.5 8.4
Change from baseline (± SE) -1.6 (±0.1)** -0.9 (±0.1)
Mean difference change from baseline between 
treatments (95% CI)

-0.67 (-0.94, -0.39)**

Patients (%) achieving HbA1c < 7% 58 30
Change in fasting plasma glucose (mmol/L) (± SE) -1.4 (±0.2) -0.3 (±0.2)
Mean body weight (kg)
Baseline 97 94
Change from baseline (± SE) -2.3 (±0.4) -1.4 (± 0.4)
Mean difference change from baseline between 
treatments (95% CI)

-0.95 (-1.91, 0.01)

30-Week Study

N 148 147
Mean HbA1c (%)
Baseline 8.3 8.3
Change from baseline (± SE) -1.9 (±0.1)* -1.5 (±0.1)
Mean difference change from baseline between 
treatments (95 % CI)

-0.33 (-0.54, -0.12)*

Patients (%) achieving HbA1c ≤ 7% 73 57
Change in fasting plasma glucose (mmol/L) (± SE) -2.3 (±0.2) -1.4 (±0.2)
Mean body weight (kg)
Baseline 102 102
Change from baseline (± SE) -3.7 (±0.5) -3.6 (±0.5)
Mean difference change from baseline between 
treatments (95% CI)

-0.08 (-1.29, 1.12)

SE = standard error, CI = confidence interval, * p < 0.05, **p < 0.0001

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 HbA1c, significantly lowered mean body weight and was 
associated with fewer hypoglycaemic events (Table 3).



33

Table 3: Results of one 26-week study of prolonged-release exenatide versus insulin glargine in 
combination with metformin alone or metformin and sulphonylurea (intent to treat patients)

Prolonged-
release exenatide
2 mg 

Insulin 

glargine
1

N 233 223
Mean HbA1c (%)
Baseline 8.3 8.3
Change from baseline (± SE) -1.5 (± 0.1)* -1.3 (± 0.1)*
Mean difference change from baseline between 
treatments (95% CI)

-0.16 (-0.29, -0.03)*

Patients (%) achieving HbA1c ≤ 7% 62 54
Change in fasting serum glucose (mmol/L) (± SE) -2.1 (± 0.2) -2.8 (± 0.2)
Mean body weight (kg)
Baseline 91 91
Change from baseline (± SE) -2.6 (± 0.2) +1.4 (±0.2)
Mean difference change from baseline between 
treatments (95% CI)

-4.05 (-4.57, -3.52)*

SE = standard error, CI = confidence interval, * p < 0.05
1
Insulin glargine was dosed to a target glucose concentration of 4.0 to 5.5 mmol/L (72 to 100 mg/dL). 

The mean dose of insulin glargine at the beginning of treatment was 10.1 IU/day rising to 31.1 IU/day 
for insulin glargine-treated patients.

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 HbA1c compared to baseline. Prolonged-release exenatide demonstrated superiority to 
both sitagliptin and pioglitazone with respect to change in HbA1c from baseline.

Prolonged-release exenatide demonstrated significantly greater weight reductions compared to 
sitagliptin. Patients on pioglitazone gained weight (Table 4).



34

Table 4: Results of one 26-week study of prolonged-release exenatide versus sitagliptin and 
versus pioglitazone in combination with metformin (intent to treat patients)

Prolonged-
release 
exenatide
2 mg

Sitagliptin 
100 mg

Pioglitazone 
45 mg

N 160 166 165
Mean HbA1c (%)
Baseline 8.6 8.5 8.5
Change from baseline (± SE) -1.6 (± 0.1)* -0.9 (± 0.1)* -1.2 (± 0.1)*
Mean difference change from baseline 
between treatments (95% CI) versus 
sitagliptin

-0.63 (-0.89, -0.37)**

Mean difference change from baseline 
between treatments (95% CI) versus 
pioglitazone

-0.32 (-0.57, -0.06)*

Patients (%) achieving HbA1c ≤ 7% 62 36 49
Change in fasting serum glucose 
(mmol/L) (± SE)

-1.8 (± 0.2) -0.9 (± 0.2) -1.5 (± 0.2)

Mean body weight (kg)
Baseline 89 87 88
Change from baseline (± SE) -2.3 (± 0.3) -0.8 (± 0.3) +2.8 (± 0.3)
Mean difference change from baseline 
between treatments (95% CI) versus 
sitagliptin

-1.54 (-2.35, -0.72)*

Mean difference change from baseline 
between treatments (95% CI) versus 
pioglitazone

-5.10 (-5.91, -4.28)**

SE = standard error, CI = confidence interval), * p<0.05, **p< 0.0001

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 HbA1c compared to baseline. The 
prolonged-release exenatide and dapagliflozin treatment group showed superior reductions in HbA1c 
from baseline compared to prolonged-release exenatide alone and dapagliflozin alone (Table 5).

The combination of prolonged-release exenatide and dapagliflozin demonstrated significantly greater 
weight reductions compared to either medicinal product alone (Table 5).



35

Table 5: Results of one 28-week study of prolonged-release exenatide and dapagliflozin versus 
prolonged-release exenatide alone and dapagliflozin alone, in combination with metformin 
(intent to treat patients)

Prolonged-release 
exenatide 2 mg QW

+
Dapagliflozin 10 mg 

QD

Prolonged-release 
exenatide 2 mg 

QW
+

Placebo QD

Dapagliflozin 
10 mg QD

+
Placebo QW

N 228 227 230
Mean HbA1c (%)
Baseline 9.3 9.3 9.3
Change from baseline (±SE)
a -2.0 (±0.1) -1.6 (±0.1) -1.4 (±0.1)

Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-0.38*

(-0.63, -0.13)

-0.59**

(-0.84, -0.34)

Patients (%) achieving 
HbA1c 7%

45 27 19

Mean change from baseline 
in fasting plasma glucose 
(mmol/L) (±SE)a

-3.7 (±0.2) -2.5 (±0.2) -2.7 (±0.2)

Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95%CI)

-1.12**
(-1.55, -0.68)

-0.92**
(-1.36, -0.49)

Mean change from baseline 
in 2-hour postprandial 
plasma glucose (mmol/L) 
(SE)a

-4.9 (±0.2) -3.3 (±0.2) -3.4 (±0.2)

Mean difference in change 
from baseline between 
combination and single 
active medicinal product  
(95% CI)

-1.54**
(-2.10, -0.98)

-1.49**
(-2.04, -0.93)

Mean body weight (kg)
Baseline 92 89 91

Change from baseline (±SE)a -3.6 (±0.3) -1.6 (±0.3) -2.2 (±0.3)
Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-2.00**

(-2.79, -1.20)

-1.33**

(-2.12, -0.55)

QW=once weekly, QD=once daily, SE = standard error, CI= confidence interval, N=number of 
patients.
a Adjusted least squares means (LS Means) and treatment group difference(s) in the change from 

baseline values at Week 28 are modelled using a mixed model with repeated measures (MMRM) 

including treatment, region, baseline HbA1c stratum (< 9.0% or ≥ 9.0%), week, and treatment by 

week interaction as fixed factors, and baseline value as a covariate.

*p < 0.01, **p < 0.001.

p-values are all adjusted p-values for multiplicity.
Analyses exclude measurements post rescue therapy and post premature discontinuation of study 
medicinal product.



36

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 HbA1c from baseline to 
Week 28 (Table 6).

Prolonged-release exenatide was superior to placebo in reducing body weight at Week 28 (Table 6).

Table 6: Results of one 28-week study of prolonged-release exenatide versus placebo in 
combination with insulin glargine alone or with metformin (intent to treat patients)

Prolonged-release 
exenatide 2 mg 
+ Insulin glarginea

Placebo
+ Insulin glarginea

N 230 228
Mean HbA1c (%)
Baseline 8.5 8.5

Change from baseline (± SE)b -1.0 (±0.1) -0.2 (±0.1)

Mean difference in change from baseline 
between treatments (95% CI)

-0.74*

(-0.94, -0.54)

Patients (%) achieving HbA1c ≤ 7%c 33* 7

Mean body weight (kg)
Baseline 94 94

Change from baseline (± SE)b -1.0 (±0.3) 0.5 (±0.3)

Mean difference in change from baseline 
between treatments (95% CI)

-1.52*

(-2.19, -0.85)
Change from baseline in 2-hour postprandial 
plasma glucose (mmol/L) (± SE)b,d

-1.6 (±0.3) -0.1 (±0.3)

Mean difference in change from baseline 
between treatments (95% CI)

-1.54*

(-2.17, -0.91)
N=number of patients in each treatment group, SE = standard error, CI= confidence interval, *p-value 
< 0.001 (adjusted for multiplicity).
a. The LS means change in mean daily insulin dose was 1.6 units for the prolonged-release exenatide 

group and 3.5 units for the placebo group.
b. Adjusted LS means and treatment group difference(s) in the change from baseline values at Week 28 

are modeled using a mixed model with repeated measures (MMRM) including treatment, region, 
baseline HbA1c stratum (< 9.0% or ≥ 9.0%), baseline SU-use stratum (yes vs. no), week, and 
treatment by week interaction as fixed factors, and baseline value as a covariate. The absolute change 
in 2-hour postprandial plasma glucose at Week 28 is modeled similarly using ANCOVA.

c. All patients with missing endpoint data are imputed as non-responders.
d. After a standard meal tolerance test.

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

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 randomised 1:1 to either prolonged-release exenatide
2 mg 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 HbA1c was 8.1%. Approximately 49.3% had mild renal impairment (estimated glomerular 



37

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.

Figure 1: Time to First Adjudicated MACE (intent to treat patients) 

HR=hazard ratio, CI=confidence interval

Figure 2: Forest Plot: Analysis of Primary and Secondary Endpoints (intent to treat patients)

MACE

All-cause death

CV-related death

Myocardial Infarction

Stroke

Hospitalisation for ACS

Hospitalisation for HF

Hazard Ratio    Exenatide Placebo

n (%)                    Event Rate      n (%)                     Event Rate   HR (95% CI)1

       <-Exenatide favored-     -Placebo favored->

)

         Exenatide
         Placebo

Exenatide vs Placebo:
HR (95% CI)                 0.91 (0.832, 1.004)

Number at Risk
Months from Randomization

P
at

ie
nt

s 
w

it
h 

an
 E

ve
nt

 (
%

)

Exenatide

Placebo



38

ACS=acute coronary syndrome; CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazard 
ratio; MACE=major adverse cardiac event; MI=myocardial infarction; n=number of patients with an event; 
N=number of patients in treatment group.

1 HR (active/placebo) and CI are based on Cox proportional hazards regression model, stratified by prior CV 
event, with treatment group only as explanatory variable.

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 HbA1c 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 all prolonged-release exenatide 
studies. In the 4 comparator-controlled studies, this reduction in body weight was seen in patients 
treated with prolonged-release exenatide irrespective of the occurrence of nausea although the 
reduction was larger in the group with nausea (mean reduction of -2.9 kg to -5.2 kg with nausea 
versus -2.2 kg to -2.9 kg without nausea).

In the 4 comparator-controlled studies, the proportion of patients who had both a reduction in weight 
and HbA1c ranged from 70 to 79% (the proportion of patients who had a reduction of HbA1c ranged 
from 88 to 96%). 

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. The improvement in fasting 
plasma glucose concentrations was durable through 52 weeks.

Beta-cell function 
Clinical studies with prolonged-release exenatide have indicated improved beta-cell function, using 
measures such as the homeostasis model assessments (HOMA-B). The durability of effect on beta-cell 
function was maintained through 52 weeks.

Blood pressure
A reduction in systolic blood pressure was observed in the 4 comparator-controlled prolonged-release 
exenatide studies (2.9 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
Prolonged-release exenatide has shown no negative effects on lipid parameters. 



39

Paediatric population
The European Medicines Agency has deferred the obligation to submit the results of studies with 
prolonged-release exenatide in one or more subsets of the paediatric population in type 2 diabetes 
mellitus (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

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 in this section).

Absorption
Following weekly administration of 2 mg prolonged-release exenatide, mean exenatide concentrations 
exceeded minimal efficacious concentrations (~ 50 pg/mL) in 2 weeks with gradual increase in the 
average plasma exenatide concentration over 6 to 7 weeks. Subsequently, exenatide concentrations of 
approximately 151-265 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
Population pharmacokinetic analysis of renal impaired patients receiving 2 mg prolonged-release 
exenatide indicate that there may be an increase in systemic exposure of approximately 74% and 23% 
(median prediction in each group) in moderate (N = 10) and mild (N = 56) renal impaired patients, 
respectively, as compared to normal (N = 84) renal function patients. 

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 section 4.2).

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 



40

slightly lower mean AUC (16% lower) and Cmax (25% lower) compared to those observed in adults. 
No pharmacokinetics study of prolonged-release exenatide has been conducted in the paediatric 
population.

5.3 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 or 
prolonged-release exenatide. 

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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder
poly (D,L-lactide-co-glycolide)
sucrose

Solvent
carmellose sodium 
sodium chloride
polysorbate 20
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections
sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal 
products.

6.3 Shelf life

3 years

After suspension
The suspension must be injected immediately after mixing the powder and the solvent. 

6.4 Special precautions for storage

Store in a refrigerator (2 ºC - 8 ºC).
Do not freeze.

The pens may be kept for up to 4 weeks below 30 ºC prior to use. At the end of this period the pens 
must be used or discarded.

Store in the original package in order to protect from light.



41

For storage conditions after mixing of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Each dual-chamber pen contains exenatide powder and solvent in a Type 1 glass cartridge sealed at 
one end with a chlorobutyl rubber stopper and an aluminium seal, and at the other end with a 
chlorobutyl rubber piston. The two chambers are separated by a second chlorobutyl rubber piston. 
There is one needle supplied per pen. Each carton also contains one spare needle. Use only the 
supplied needles with the pen.

Pack size of 4 single-dose pre-filled pens and a multipack containing 12 (3 packs of 4) single-dose 
pre-filled pens.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Pre-filled pen is for single-use only.

The pen must be removed from the refrigerator for at least 15 minutes prior to injection. The powder 
in one chamber must be mixed with the solvent in the other chamber of the pre-filled pen. The solvent 
should be visually inspected prior to use. The solvent should only be used if it is clear and free of 
particulate matter. After suspension, the mixture should only be used if it is white to off white and 
cloudy. Please see the package leaflet and “Instructions for the User” for additional information on 
suspension and administration.

Use only the supplied custom needles with the pen.

Prolonged-release exenatide must be injected subcutaneously immediately after mixing of the powder 
and the solvent.

Prolonged-release exenatide that has been frozen must not be used. 

The patient should be instructed to discard the pen safely, with the needle still attached, after each 
injection. 

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/003-004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 June 2011
Date of latest renewal: 18 February 2016



42

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu

http://www.ema.europa.eu/


43

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg prolonged-release suspension for injection in pre-filled pen.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each pre-filled pen delivers a dose of 2 mg of exenatide in 0.85 mL.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Prolonged-release suspension for injection in pre-filled pen (BCise).

White to off-white opaque suspension.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

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 studied, see sections 4.4, 4.5, and 5.1.

4.2 Posology and method of administration

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 section 4.4).

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. 



44

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 section 5.2).

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) (see section 5.2).

Renal impairment
No dose adjustment is necessary for patients with mild or moderate renal impairment.

Prolonged-release exenatide is not recommended for use in patients with end-stage renal disease or 
severe renal impairment (glomerular filtration rate [GFR] < 30mL/min) (see section 4.4).

Hepatic impairment
No dose adjustment is necessary for patients with hepatic impairment (see section 5.2).

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 section 5.2 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 pen 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 section 6.6 and 
the “Instructions for the User”.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

Prolonged-release exenatide should not be used in patients with type 1 diabetes mellitus or for the 
treatment of diabetic ketoacidosis.



45

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 section 4.2). 

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 (GFR < 30mL/min). 

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 section 4.5).

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.



46

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.

4.5 Interaction with other medicinal products and other forms of interaction

Sulphonylureas
The dose of a sulphonylurea may require adjustment due to the increased risk of hypoglycaemia 
associated with sulphonylurea therapy (see sections 4.2 and 4.4). 

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 Cmax decreased by 16% (fasting) and 5% (fed) 
and tmax 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 tmax of about 2 h was observed when warfarin was administered 35 min after 
immediate-release exenatide. No clinically relevant effects on Cmax 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 sections 4.4 and 4.8).

Hydroxy methyl glutaryl coenzyme A reductase inhibitors
Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and tmax 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 
section 5.1). 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 Cmax or AUC, however, a delay in tmax 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, Cmax or Cmin 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 Cmax of ethinyl estradiol by 45%, and 
Cmax of levonorgestrel by 27-41%, and a delay in tmax by 2-4 h due to delayed gastric emptying. The 
reduction in Cmax is of limited clinical relevance and no adjustment of dosing of oral contraceptives is 
required.



47

Paediatric population
Interaction studies with exenatide have only been performed in adults.

4.6 Fertility, pregnancy and lactation

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 section 5.3). 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.

4.7 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.

4.8 Undesirable effects

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, below). 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 1 below.

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 1. 

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 below 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), 



48

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).

Table 1: Adverse reactions of Bydureon BCise identified from clinical studies

System organ class 
/adverse reaction 
terms

Frequency of occurrence1

Very 
common

Common Uncommon Rare Very rare Not 
known

Blood and lymphatic system disorders
Drug-induced 
thrombocytopenia9

X

Immune system disorders
Anaphylactic reaction2 X
Metabolism and nutrition disorders
Hypoglycaemia (with 
a sulphonylurea)5,6,7

X

Hypoglycaemia 
(without a 
sulphonylurea)5,6,7

X

Hypoglycaemia (with 
insulin)3,4,5

X

Decreased appetite X
Dehydration X
Nervous system disorders
Headache X
Dizziness X
Dysgeusia X
Somnolence2 X
Gastrointestinal disorders
Nausea5 X
Diarrhoea X
Vomiting X
Constipation X
Dyspepsia X
Gastroesophageal 
reflux disease

X

Abdominal distension X
Abdominal pain X
Flatulence X
Acute pancreatitis (see 
section 4.4)

X

Eructation2 X
Intestinal obstruction2 X
Skin and subcutaneous tissue disorders
Urticaria X
Hyperhidrosis X
Macular or papular 
rash

X

Pruritus X
Alopecia2 X
Angioedema 9 X



49

System organ class 
/adverse reaction 
terms

Frequency of occurrence1

Very 
common

Common Uncommon Rare Very rare Not 
known

Injection site abscesses 
and cellulitis9

X

Renal and urinary disorders
Altered renal function8 X
General disorders and administration site conditions
Injection site pruritus5 X
Injection site 
erythema5

X

Fatigue X
Injection site reaction5 X
Asthenia X
Injection site rash5 X
Feeling jittery2 X
Investigations

International 
normalised ratio 
increased9 (see section 
4.4)

X

1 Rate based on completed long-term safety and efficacy studies (n = 526), unless other indicated. 
Includes follow-up within seventy days of the last dose received and extension period. 
2 Rate based on twelve prolonged-release exenatide completed long-term efficacy and safety studies 
n = 2868 total. 
3 Based on hypoglycaemic events that 1. Result in loss of consciousness, seizure, or coma which 
resolves after administration of glucagon or glucose OR 2. Require third-party assistance to resolve 
because of impairment in consciousness or behaviour and has glucose value of < 54 mg/dL 
(3 mmol/L) OR 3. Result in symptoms consistent with hypoglycaemia with a concomitant glucose 
< 54 mg/dL (3 mmol/L) prior to treatment.
4. Frequency reported from the 28-week controlled treatment period of the prolonged-release exenatide 
as add on to insulin glargine study (N=231).
5 See Description of selected adverse reactions section, below.
6 Frequencies reported in pooled data from the controlled periods of the two phase 3 clinical studies 
(n = 410).
7 Based on hypoglycaemic events that have symptoms consistent with hypoglycaemia with a 
concomitant glucose value of < 54 mg/dL (3 mmol/L) prior to treatment.
8 Includes acute renal failure, worsened chronic renal failure, renal impairment, increased serum 
creatinine. See section 4.4.
9 Rate based on prolonged-release exenatide spontaneous reports data (unknown denominator). 

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 section 4.4). To reduce the risk of 



50

hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea may 
be considered (see sections 4.2 and 4.4).

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 (HbA1c) 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 HbA1c response, HbA1c
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 



51

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 via the national reporting system 
listed in Appendix V.

4.9 Overdose

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. 

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes, glucagon-like peptide-1 (GLP-1) analogues, ATC 
code: A10BJ01.

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 section 
4.4).

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.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


52

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 below; 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 HbA1c compared to baseline. Bydureon 
BCise demonstrated superiority to immediate-release exenatide in reducing HbA1c from baseline to 
Week 28 (Table 2). 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 HbA1c 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 2). The difference between the two treatment groups was not 
significant. The reductions in body weight were sustained at Week 52.

Table 2: Results of one 28-week study of Bydureon BCise versus immediate-release exenatide 
with diet and exercise alone or with a stable regimen of oral glucose-lowering medicinal 
products (modified intent to treat patients1)

Bydureon BCise 2 mg 
QW

Immediate-release 
exenatide 10 mcg 
BID

N 229 146
Mean HbA1c (%)
Baseline 8.5 8.5
Change from baseline (± SE)2 -1.4 (±0.1) -1.0 (±0.1)
Mean difference in change from baseline 
versus immediate-release exenatide (95% 
CI)2

-0.37*
(-0.63, -0.10)

Patients (%) achieving HbA1c < 7%3 49 43
Mean body weight (kg)
Baseline 97 97
Change from baseline (± SE)2 -1.5 (±0.3) -1.9 (±0.4)
Mean difference in change from baseline 
versus immediate-release exenatide (95% 
CI)2

+0.40
(-0.48, 1.28)

Mean change from baseline in fasting plasma 
glucose (mmol/L) (± SE)2

-1.8 (±0.2) -1.3 (±0.3)

Mean difference in change from baseline 
versus immediate-release exenatide (95% 
CI)2

-0.56
(-1.20, 0.08)

QW = once weekly, BID = twice daily, N = number of patients per treatment group, SE = standard 
error, CI = confidence interval.
*p-value < 0.01.



53

1 All randomised patients who received at least one dose of study medication.
2 Least squares means.
3 Last Observation Carried Forward (LOCF).

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 HbA1c from baseline to Week 28 (Table 3).

Both Bydureon BCise and sitagliptin patients achieved a reduction in weight at Week 28 compared to 
baseline (Table 3). The difference between the two treatment groups was not significant. 

Table 3: Results of one 28-week study of Bydureon BCise versus sitagliptin and placebo in 
combination with metformin (modified intent to treat patients1)

Bydureon BCise 
2 mg QW

Sitagliptin 
100 mg QD

Placebo QD

N 181 122 61
Mean HbA1c (%)

Baseline 8.4 8.5 8.5
Change from baseline (± SE)2 -1.1 (± 0.1) -0.8 (± 0.1) -0.4 (± 0.2)
Mean difference in change from 
baseline versus sitagliptin (95% CI)2

-0.38*
(-0.70, -0.06)

Mean difference in change from 
baseline versus placebo (95% CI)2

-0.72**
(-1.15, -0.30)

Patients (%) achieving HbA1c < 7%3 43* 32 25
Mean body weight (kg)

Baseline 89 88 89
Change from baseline (± SE)2 -1.1 (± 0.3) -1.2 (± 0.3) +0.2 (± 0.5)
Mean difference in change from 
baseline versus sitagliptin (95% CI)2

+0.07
(-0.73, 0.87)

Mean difference in change from 
baseline versus placebo (95% CI)2

-1.27#

(-2.34, -0.20)
Mean change from baseline in fasting 
plasma glucose (mmol/L) (± SE)2

-1.2 (±0.2) -0.6 (±0.3) +0.5 (±0.4)

Mean difference in change from 
baseline versus sitagliptin (95% CI)2

-0.56
(-1.21, 0.09)

Mean difference in change from 
baseline versus placebo (95% CI)2

-1.71§

(-2.59, -0.83)
QW = once weekly, QD = once daily, N = number of patients per treatment group, SE = standard 
error, CI = confidence interval.
*p-value < 0.05, **p-value < 0.01, #nominal p-value < 0.05, §nominal p-value < 0.001.
1 All randomised patients who received at least one dose of study medication.
2 Least squares means.
3 Last Observation Carried Forward (LOCF).

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 HbA1c were 
evident in both treatment groups as early as the first post-treatment HbA1c measurement (Weeks 4 or 
6).



54

Prolonged-release exenatide resulted in a statistically significant reduction in HbA1c compared to 
patients receiving immediate-release exenatide (Table 4).

A clinically relevant effect of prolonged-release exenatide and immediate-release exenatide treated 
subjects was observed on HbA1c, 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 HbA1c 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 HbA1c 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), HbA1c 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.

Table 4: Results of two studies of prolonged-release versus immediate-release exenatide in 
combination with diet and exercise alone, metformin and/or sulphonylurea and metformin 
and/or thiazolidinedione (intent to treat patients)

24-Week Study Prolonged-
release 
exenatide 2 mg 

Immediate-
release 
exenatide 
10 mcg twice 
daily

N 129 123
Mean HbA1c (%)
Baseline 8.5 8.4
Change from baseline (± SE) -1.6 (±0.1)** -0.9 (±0.1)
Mean difference change from baseline between 
treatments (95% CI)

-0.67 (-0.94, -0.39)**

Patients (%) achieving HbA1c < 7% 58 30
Change in fasting plasma glucose (mmol/L) (± SE) -1.4 (±0.2) -0.3 (±0.2)
Mean body weight (kg)
Baseline 97 94
Change from baseline (± SE) -2.3 (±0.4) -1.4 (± 0.4)
Mean difference change from baseline between 
treatments (95% CI)

-0.95 (-1.91, 0.01)

30-Week Study

N 148 147
Mean HbA1c (%)
Baseline 8.3 8.3
Change from baseline (± SE) -1.9 (±0.1)* -1.5 (±0.1)
Mean difference change from baseline between 
treatments (95% CI)

-0.33 (-0.54, -0.12)*

Patients (%) achieving HbA1c ≤ 7% 73 57
Change in fasting plasma glucose (mmol/L) (± SE) -2.3 (±0.2) -1.4 (±0.2)
Mean body weight (kg)
Baseline 102 102
Change from baseline (± SE) -3.7 (±0.5) -3.6 (±0.5)



55

24-Week Study Prolonged-
release 
exenatide 2 mg 

Immediate-
release 
exenatide 
10 mcg twice 
daily

Mean difference change from baseline between 
treatments (95% CI)

-0.08 (-1.29, 1.12)

SE = standard error, CI = confidence interval, * p < 0.05, **p < 0.0001

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 HbA1c, significantly lowered mean body weight and was 
associated with fewer hypoglycaemic events (Table 5).

Table 5: Results of one 26-week study of prolonged-release exenatide versus insulin glargine in 
combination with metformin alone or metformin and sulphonylurea (intent to treat patients)

Prolonged-
release 
exenatide
2 mg 

Insulin 

glargine
1

N 233 223
Mean HbA1c (%)
Baseline 8.3 8.3
Change from baseline (± SE) -1.5 (± 0.1)* -1.3 (± 0.1)*
Mean difference change from baseline between 
treatments (95% CI)

-0.16 (-0.29, -0.03)*

Patients (%) achieving HbA1c ≤ 7% 62 54
Change in fasting serum glucose (mmol/L) (± SE) -2.1 (± 0.2) -2.8 (± 0.2)
Mean body weight (kg)
Baseline 91 91
Change from baseline (± SE) -2.6 (± 0.2) +1.4 (±0.2)
Mean difference change from baseline between 
treatments (95% CI)

-4.05 (-4.57, -3.52)*

SE = standard error, CI = confidence interval, * p < 0.05
1
Insulin glargine was dosed to a target glucose concentration of 4.0 to 5.5 mmol/L (72 to 100 mg/dL).

The mean dose of insulin glargine at the beginning of treatment was 10.1 IU/day rising to 31.1 IU/day 
for insulin glargine-treated patients.

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 HbA1c compared to baseline. Prolonged-release exenatide demonstrated superiority to 
both sitagliptin and pioglitazone with respect to change in HbA1c from baseline. 

Prolonged-release exenatide demonstrated significantly greater weight reductions compared to 
sitagliptin. Patients on pioglitazone gained weight (Table 6).



56

Table 6: Results of one 26-week study of prolonged-release exenatide versus sitagliptin and 
versus pioglitazone in combination with metformin (intent to treat patients)

Prolonged-
release 
exenatide
2 mg

Sitagliptin 
100 mg

Pioglitazone 
45 mg

N 160 166 165
Mean HbA1c (%)
Baseline 8.6 8.5 8.5
Change from baseline (± SE) -1.6 (± 0.1)* -0.9 (± 0.1)* -1.2 (± 0.1)*
Mean difference change from baseline 
between treatments (95% CI) versus 
sitagliptin

-0.63 (-0.89, -0.37)**

Mean difference change from baseline 
between treatments (95% CI) versus 
pioglitazone

-0.32 (-0.57, -0.06)*

Patients (%) achieving HbA1c ≤ 7% 62 36 49
Change in fasting serum glucose 
(mmol/L) (± SE)

-1.8 (± 0.2) -0.9 (± 0.2) -1.5 (± 0.2)

Mean body weight (kg)
Baseline 89 87 88
Change from baseline (± SE) -2.3 (± 0.3) -0.8 (± 0.3) +2.8 (± 0.3)
Mean difference change from baseline 
between treatments (95% CI) versus 
sitagliptin

-1.54 (-2.35, -0.72)*

Mean difference change from baseline 
between treatments (95% CI) versus 
pioglitazone

-5.10 (-5.91, -4.28)**

SE = standard error, CI = confidence interval, *p < 0.05, **p < 0.0001

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 HbA1c compared to baseline. The 
prolonged-release exenatide and dapagliflozin treatment group showed superior reductions in HbA1c 
from baseline compared to prolonged-release exenatide alone and dapagliflozin alone (Table 7). 

The combination of prolonged-release exenatide and dapagliflozin demonstrated significantly greater 
weight reductions compared to either medicinal product alone (Table 7).



57

Table 7: Results of one 28-week study of prolonged-release exenatide and dapagliflozin versus 
prolonged-release exenatide alone and dapagliflozin alone, in combination with metformin 
(intent to treat patients)

Prolonged-release 
exenatide 2 mg QW

+
Dapagliflozin 10 mg 

QD

Prolonged-release 
exenatide 2 mg 

QW
+

Placebo QD

Dapagliflozin 
10 mg QD

+
Placebo QW

N 228 227 230
Mean HbA1c (%)
Baseline 9.3 9.3 9.3

Change from baseline (±SE)a -2.0 (±0.1) -1.6 (±0.1) -1.4 (±0.1)
Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-0.38*

(-0.63, -0.13)

-0.59**

(-0.84, -0.34)

Patients (%) achieving 
HbA1c 7%

45 27 19

Mean change from baseline 
in fasting plasma glucose 
(mmol/L) (±SE)a

-3.7 (±0.2) -2.5 (±0.2) -2.7 (±0.2)

Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-1.12**
(-1.55, -0.68)

-0.92**
(-1.36, -0.49)

Mean change from baseline 
in 2-hour postprandial 
plasma glucose (mmol/L) 
(SE) a

-4.9 (±0.2) -3.3 (±0.2) -3.4 (±0.2)

Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-1.54**
(-2.10, -0.98)

-1.49**
(-2.04, -0.93)

Mean body weight (kg)
Baseline 92 89 91

Change from baseline (±SE)a -3.6 (±0.3) -1.6 (±0.3) -2.2 (±0.3)
Mean difference in change 
from baseline between 
combination and single 
active medicinal product 
(95% CI)

-2.00**

(-2.79, -1.20)

-1.33**

(-2.12, -0.55)

QW=once weekly, QD=once daily, SE = standard error, CI= confidence interval, N=number of 
patients.
a Adjusted least squares means (LS Means) and treatment group difference(s) in the change from 

baseline values at Week 28 are modelled using a mixed model with repeated measures (MMRM) 

including treatment, region, baseline HbA1c stratum (< 9.0% or ≥ 9.0%), week, and treatment by 

week interaction as fixed factors, and baseline value as a covariate.

*p < 0.01, **p < 0.001.

p-values are all adjusted p-values for multiplicity.

Analyses exclude measurements post rescue therapy and post premature discontinuation of study 
medicinal product.



58

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 HbA1c from baseline to 
Week 28 (Table 8).

Prolonged-release exenatide was superior to placebo in reducing body weight at Week 28 (Table 8).

Table 8: Results of one 28-week study of prolonged-release exenatide versus placebo in 
combination with insulin glargine alone or with metformin (intent to treat patients)

Prolonged-release 
exenatide 2 mg 
+ Insulin glarginea

Placebo
+ Insulin glarginea

N 230 228
Mean HbA1c (%)
Baseline 8.5 8.5

Change from baseline (± SE)b -1.0 (±0.1) -0.2 (±0.1)

Mean difference in change from baseline 
between treatments (95% CI)

-0.74*

(-0.94, -0.54)

Patients (%) achieving HbA1c ≤ 7%c 33* 7

Mean body weight (kg)
Baseline 94 94

Change from baseline (± SE)b -1.0 (±0.3) 0.5 (±0.3)

Mean difference in change from baseline 
between treatments (95% CI)

-1.52*

(-2.19, -0.85)
Change from baseline in 2-hour postprandial 
plasma glucose (mmol/L) (± SE)b,d

-1.6 (±0.3) -0.1 (±0.3)

Mean difference in change from baseline 
between treatments (95% CI)

-1.54*

(-2.17, -0.91)
N=number of patients in each treatment group, SE = standard error, CI= confidence interval, *p-value 
< 0.001 (adjusted for multiplicity).
a. The LS means change in mean daily insulin dose was 1.6 units for the prolonged-release exenatide 
group and 3.5 units for the placebo group.
b. Adjusted LS means and treatment group difference(s) in the change from baseline values at Week 28 
are modeled using a mixed model with repeated measures (MMRM) including treatment, region, 
baseline HbA1c stratum (< 9.0% or ≥ 9.0%), baseline SU-use stratum (yes vs. no), week, and treatment 
by week interaction as fixed factors, and baseline value as a covariate. The absolute change in 2-hour 
postprandial plasma glucose at Week 28 is modeled similarly using ANCOVA.
c. All patients with missing endpoint data are imputed as non-responders.
d. After a standard meal tolerance test.

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

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 randomised 1:1 to either prolonged-release exenatide
2 mg 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. 



59

The mean HbA1c 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.

Figure 1: Time to First Adjudicated MACE (intent to treat patients) 

HR=hazard ratio, CI=confidence interval

Figure 2: Forest Plot: Analysis of Primary and Secondary Endpoints (intent to treat patients)

MACE

All-cause death

CV-related death

Myocardial Infarction

Stroke

Hospitalisation for ACS

Hospitalisation for HF

Hazard Ratio    Exenatide Placebo

n (%)                    Event Rate      n (%)                     Event Rate   HR (95% CI)1

       <-Exenatide favored-     -Placebo favored->

)

         Exenatide
         Placebo

Exenatide vs Placebo:
HR (95% CI)                 0.91 (0.832, 1.004)

Number at Risk
Months from Randomization

P
at

ie
nt

s 
w

it
h 

an
 E

ve
nt

 (
%

)

Exenatide

Placebo



60

ACS=acute coronary syndrome; CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazard 
ratio; MACE=major adverse cardiac event; MI=myocardial infarction; n=number of patients with an event; 
N=number of patients in treatment group.

1 HR (active/placebo) and CI are based on Cox proportional hazards regression model, stratified by prior CV 
event, with treatment group only as explanatory variable.

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 HbA1c 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 section 4.2 for information on paediatric use).



61

5.2 Pharmacokinetic properties

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 in this section).

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 section 4.2).

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 Cmax (25% lower) compared to those observed in adults. 
No pharmacokinetics study of prolonged-release exenatide has been conducted in the paediatric 
population.



62

5.3 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Powder
poly (D,L-lactide-co-glycolide)
sucrose

Vehicle
Medium chain triglycerides

6.2 Incompatibilities

In the absence of compatibility studies this medicinal product must not be mixed with other medicinal 
products.

6.3 Shelf life

3 years

6.4 Special precautions for storage

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

6.5 Nature and contents of container

The suspension is packaged in a 2-mL Type I glass cartridge, sealed at one end with a (bromobutyl) 
rubber seal/cap combination (combiseal), and at the other end with a (bromobuty) rubber plunger. The 
finished medicinal product is comprised of the suspension-filled cartridge assembled into the pen 
device. The pen contains an integrated needle. 

Pack size of 4 single-dose pre-filled pens (BCise) and a multipack containing 12 (3 packs of 4) 
single-dose pre-filled pens (BCise).

Not all pack sizes may be marketed.



63

6.6 Special precautions for disposal and other handling

Pre-filled pen is for single-use only.

Patients and caregivers should be trained by their healthcare professional.

The BCise pen 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 pen 
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 pen safely after each injection.

Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements.

7. MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

8. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/005-006

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 17 June 2011

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu

http://www.ema.europa.eu/


64

ANNEX II

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT



65

A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE

Name and address of the manufacturers responsible for batch release
AstraZeneca AB
Gärtunavägen
SE-151 85 Södertälje
Sweden

AstraZeneca UK Limited
Silk Road Business Park,
Macclesfield, Cheshire, SK10 2NA
United Kingdom

Swords Laboratories T/A Lawrence Laboratories
Unit 12 Distribution Centre, Shannon Industrial Estate, Shannon, Co. Clare
Ireland

The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE

Medicinal product subject to medical prescription.

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION

 Periodic Safety Update Reports

The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and any subsequent updates published on the European medicines webportal.

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 
EFFECTIVE USE OF THE MEDICINAL PRODUCT

 Risk Management Plan (RMP)

The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2. of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.

An updated RMP should be submitted:
 At the request of the European Medicines Agency;
 Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of an 
important (pharmacovigilance or risk minimisation) milestone being reached.



66

ANNEX III

LABELLING AND PACKAGE LEAFLET



67

A. LABELLING



68

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON - 4 SINGLE-DOSE KITS

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 2 mg exenatide

3. LIST OF EXCIPIENTS

Excipients:
Powder
poly (D,L-lactide-co-glycolide)
sucrose

Solvent:
carmellose sodium
sodium chloride
polysorbate 20
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for prolonged-release suspension for injection.
Each carton contains 4 single-dose kits:
1 single-dose kit contains:
1 vial of 2 mg exenatide
1 pre-filled syringe of 0.65 mL solvent
1 vial connector
2 injection needles

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Follow the Instructions for the User to prepare and inject your dose.
Subcutaneous use
Bydureon must be injected immediately after suspension of the powder in the solvent. 
Once weekly



69

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
The kit 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.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/001

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

bydureon



70

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



71

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

INNER CARTON, MULTIPACK OF 3 X (4 SINGLE-DOSE KITS) – WITH NO BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 2 mg exenatide

3. LIST OF EXCIPIENTS

Excipients:
Powder
poly (D,L-lactide-co-glycolide)
sucrose

Solvent:
carmellose sodium
sodium chloride
polysorbate 20
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for prolonged-release suspension for injection.
Part of a multi-pack of 3 x (4 single dose kits). Do not sell separately.
Each carton contains 4 single-dose kits:
1 single-dose kit contains:
1 vial of 2 mg exenatide
1 pre-filled syringe of 0.65 mL solvent
1 vial connector
2 injection needles

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Follow the Instructions for the User to prepare and inject your dose.
Subcutaneous use
Bydureon must be injected immediately after suspension of the powder in the solvent. 
Once weekly



72

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
The kit 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.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE



73

16. INFORMATION IN BRAILLE

bydureon

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



74

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON, MULTIPACK OF 3 X (4 SINGLE-DOSE KITS) - INCLUDING THE 
BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each vial contains 2 mg exenatide

3. LIST OF EXCIPIENTS

Excipients:
Powder
poly (D,L-lactide-co-glycolide)
sucrose

Solvent:
carmellose sodium
sodium chloride
polysorbate 20
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections

4. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for prolonged-release suspension for injection.
Multi-pack of 3 x (4 single dose kits). Do not sell separately.

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Follow the Instructions for the User to prepare and inject your dose.
Subcutaneous use
Bydureon must be injected immediately after suspension of the powder in the solvent. 
Once weekly

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



75

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
The kit 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.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/002

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

bydureon

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



76

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



77

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

VIAL LABEL 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Bydureon 2 mg powder for injection 
exenatide
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP 

4. BATCH NUMBER

Lot 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

2 mg

6. OTHER

AstraZeneca AB



78

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

SOLVENT LABEL

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Solvent for Bydureon

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

0.65 mL

6. OTHER

AstraZeneca AB



79

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (PACK OF 4 SINGLE-DOSE PRE-FILLED PENS)

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled pen contains 2 mg exenatide. After suspension, the delivered dose is 2 mg/0.65 mL.

3. LIST OF EXCIPIENTS

Excipients:
Powder 
poly (D,L-lactide-co-glycolide)
sucrose

Solvent:
carmellose sodium
sodium chloride
polysorbate 20
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections
sodium hydroxide

4. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for prolonged-release suspension for injection.
4 single-dose pre-filled pens
1 spare injection needle

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Follow the Instructions for the User to prepare and inject your dose.
Subcutaneous use
For single-use only
Bydureon must be injected immediately after mixing.
Once weekly

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



80

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
The pre-filled pens 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.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/003

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

bydureon

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



81

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



82

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

INNER CARTON MULTIPACK OF 3 X (4 SINGLE-DOSE PRE-FILLED PENS) – WITH NO 
BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled pen contains 2 mg exenatide. After suspension, the delivered dose is 2 mg/0.65 mL.

3. LIST OF EXCIPIENTS

Excipients:
Powder
poly (D,L-lactide-co-glycolide)
sucrose

Solvent:
carmellose sodium
sodium chloride
polysorbate 20
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections
sodium hydroxide

4. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for prolonged-release suspension for injection.
4 single-dose pre-filled pens. Component of a multipack, can’t be sold separately.
1 spare injection needle

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Follow the Instructions for the User to prepare and inject your dose.
Subcutaneous use
For single-use only
Bydureon must be injected immediately after mixing.
Once weekly



83

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
The pre-filled pens 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.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE



84

16. INFORMATION IN BRAILLE

bydureon

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



85

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON MULTIPACK OF 3 X (4 SINGLE-DOSE PRE-FILLED 
PENS) - INCLUDING THE BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled pen
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled pen contains 2 mg exenatide. After suspension, the delivered dose is 2 mg/0.65 mL

3. LIST OF EXCIPIENTS

Excipients:
Powder
poly (D,L-lactide-co-glycolide)
sucrose

Solvent:
carmellose sodium
sodium chloride
polysorbate 20
sodium dihydrogen phosphate monohydrate
disodium phosphate heptahydrate
water for injections
sodium hydroxide

4. PHARMACEUTICAL FORM AND CONTENTS

Powder and solvent for prolonged-release suspension for injection
Multipack: 12 (3 packs of 4) single-dose pre-filled pens

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Read the package leaflet before use.
Follow the Instructions for the User to prepare and inject your dose.
Subcutaneous use
For single-use only
Bydureon must be injected immediately after mixing.
Once weekly

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.



86

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
Do not freeze.
The pre-filled pens may be kept for up to 4 weeks below 30 ºC prior to use.
Store in the original package in order to protect from light.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/004

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

bydureon

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.



87

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



88

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PEN GRIP LABEL 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection 
exenatide
SC

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

2 mg

6. OTHER

AstraZeneca AB



89

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

CARTON (PACK OF 4 SINGLE-DOSE PRE-FILLED PENS)

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg prolonged-release suspension for injection in pre-filled pen 
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled pen delivers a dose of 2 mg of exenatide in 0.85 mL.

3. LIST OF EXCIPIENTS

Excipients:
Powder
poly (D,L-lactide-co-glycolide)
sucrose

Vehicle
Medium chain triglycerides (MCT)

4. PHARMACEUTICAL FORM AND CONTENTS

Prolonged-release suspension for injection
4 single-dose pre-filled pens (BCise) 
BCise

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Follow the instructions for the user to prepare and inject your dose.
Single-use only
Once weekly
Shake well before use.
Bydureon must be injected immediately after mixing and preparation.
Read the package leaflet before use.
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE



90

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
The pre-filled pen may be kept for up to 4 weeks below 30 ºC prior to use.
Store in the original package in order to protect from light.
The pre-filled pen must be stored flat.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/005

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

bydureon bcise

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC
SN
NN



91

PARTICULARS TO APPEAR ON THE INTERMEDIATE PACKAGING

INNER CARTON MULTIPACK OF 3 X (4 SINGLE-DOSE PRE-FILLED PENS) – WITH NO 
BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg prolonged-release suspension for injection in pre-filled pen
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled pen delivers a dose of 2 mg of exenatide in 0.85 mL.

3. LIST OF EXCIPIENTS

Excipients:
Powder
poly (D,L-lactide-co-glycolide)
sucrose

Vehicle
Medium chain triglycerides (MCT)

4. PHARMACEUTICAL FORM AND CONTENTS

Prolonged-release suspension for injection
4 single-dose pre-filled pens (BCise). Component of a multipack, can’t be sold separately.
BCise

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Follow the instructions for the user to prepare and inject your dose.
Single-use only
Once weekly
Shake well before use.
Bydureon must be injected immediately after mixing and preparation.
Read the package leaflet before use.
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY

8. EXPIRY DATE



92

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
The pre-filled pen may be kept for up to 4 weeks below 30 ºC prior to use.
Store in the original package in order to protect from light.
The pre-filled pen must be stored flat.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

bydureon bcise

17. UNIQUE IDENTIFIER – 2D BARCODE

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA



93

PARTICULARS TO APPEAR ON THE OUTER PACKAGING

OUTER CARTON MULTIPACK OF 3 X (4 SINGLE-DOSE PRE-FILLED 
PENS) - INCLUDING THE BLUE BOX

1. NAME OF THE MEDICINAL PRODUCT

Bydureon 2 mg prolonged-release suspension for injection in pre-filled pen 
exenatide

2. STATEMENT OF ACTIVE SUBSTANCE(S)

Each pre-filled pen delivers a dose of 2 mg of exenatide in 0.85 mL.

3. LIST OF EXCIPIENTS

Excipients:
Powder
poly (D,L-lactide-co-glycolide)
sucrose

Vehicle
Medium chain triglycerides (MCT)

4. PHARMACEUTICAL FORM AND CONTENTS

Prolonged-release suspension for injection
Multipack: 12 (3 packs of 4) single-dose pre-filled pens (BCise)
BCise

5. METHOD AND ROUTE(S) OF ADMINISTRATION

Follow the instructions for the user to prepare and inject your dose.
Single-use only
Once weekly
Shake well before use.
Bydureon must be injected immediately after mixing and preparation.
Read the package leaflet before use.
Subcutaneous use

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
OF THE SIGHT AND REACH OF CHILDREN

Keep out of the sight and reach of children.

7. OTHER SPECIAL WARNING(S), IF NECESSARY



94

8. EXPIRY DATE

EXP

9. SPECIAL STORAGE CONDITIONS

Store in a refrigerator.
The pre-filled pen may be kept for up to 4 weeks below 30 ºC prior to use.
Store in the original package in order to protect from light.
The pre-filled pen must be stored flat.

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER

AstraZeneca AB
SE-151 85 Södertälje
Sweden

12. MARKETING AUTHORISATION NUMBER(S) 

EU/1/11/696/006

13. BATCH NUMBER

Lot

14. GENERAL CLASSIFICATION FOR SUPPLY

15. INSTRUCTIONS ON USE

16. INFORMATION IN BRAILLE

bydureon bcise

17. UNIQUE IDENTIFIER – 2D BARCODE

2D barcode carrying the unique identifier included.

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA

PC



95

SN
NN



96

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS

PRE-FILLED PEN LABEL 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION

Bydureon 2 mg prolonged-release suspension for injection
exenatide
SC
BCise

2. METHOD OF ADMINISTRATION

3. EXPIRY DATE

EXP

4. BATCH NUMBER

Lot

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT

2 mg

6. OTHER

AstraZeneca AB



97

B. PACKAGE LEAFLET



98

Package Leaflet: Information for the user

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection
exenatide

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist, or diabetes nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist, or diabetes nurse. This includes any 

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Bydureon is and what it is used for
2. What you need to know before you use Bydureon
3. How to use Bydureon
4. Possible side effects
5. How to store Bydureon
6. Contents of the pack and other information

1. What Bydureon is and what it is used for

Bydureon contains the active substance exenatide. It is an injectable medicine used to improve blood 
sugar control in adults with type 2 diabetes mellitus.

This medicine is used in combination with the following diabetes medicines: metformin, 
sulphonylureas, thiazolidinediones, SGLT2 inhibitors and/or a long-acting insulin. Your doctor is now 
prescribing this medicine as an additional medicine to help control your blood sugar. Continue to 
follow your food and exercise plan.

You have diabetes because your body does not make enough insulin to control the level of sugar in 
your blood or your body is not able to use the insulin properly. This medicine helps your body to 
increase the production of insulin when your blood sugar is high. 

2. What you need to know before you use Bydureon

Do not use Bydureon:
- If you are allergic to exenatide or any of the other ingredients of this medicine (listed in section 

6).

Warnings and precautions
Talk to your doctor, pharmacist, or diabetes nurse before using Bydureon about the following:
- If you use this medicine in combination with a sulphonylurea, as low blood sugar 

(hypoglycaemia) can occur. Test your blood glucose levels regularly. Ask your doctor, 
pharmacist, or diabetes nurse if you are not sure if any of your other medicines contain a 
sulphonylurea.

- If you have type 1 diabetes or diabetic ketoacidosis, as this medicine should not be used.
- How to inject this medicine. It should be injected into the skin and not into a vein or into the 

muscle. 
- If you have severe problems with your stomach emptying (including gastroparesis) or food 

digestion, as the use of this medicine is not recommended. The active substance in this medicine 
slows stomach emptying so food passes more slowly through your stomach.



99

- If you have ever had inflammation of the pancreas (pancreatitis) (see section 4).
- If you lose weight too quickly (more than 1.5 kg per week) talk to your doctor about it since this 

may cause problems such as gallstones.
- If you have severe kidney disease or you are on dialysis, as the use of this medicine is not 

recommended.

Bydureon is not an insulin and should therefore not be used as a substitute for insulin. 

Children and adolescents
Do not give this medicine to children and adolescents less than 18 years, as there is no experience with 
this medicine in this age group.

Other medicines and Bydureon
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines, particularly:
- other medicines that are used to treat type 2 diabetes, such as medicines that work like 

Bydureon (for example: liraglutide or other exenatide containing products), as taking these 
medicines with Bydureon is not recommended.

- medicines used to thin the blood (anticoagulants), e.g. Warfarin, as you will require additional 
monitoring of changes in INR (measurement of blood thinning) during initiation of therapy with 
this medicine.

- a medicine that contains a sulphonylurea, as low blood sugar (hypoglycaemia) can occur when 
combined with Bydureon. 

- if you are using insulin, your doctor will tell you how to reduce the dose of insulin and will 
recommend that you monitor your blood sugar more frequently, in order to avoid 
hyperglycaemia (high blood sugar) and diabetic ketoacidosis (a complication of diabetes that 
occurs when the body is unable to break down glucose because there is not enough insulin).

Pregnancy and breast-feeding
It is not known if this medicine may harm your unborn child, therefore you should not use it during 
pregnancy and for at least 3 months before a planned pregnancy.

It is not known if exenatide passes into your milk. You should not use this medicine while 
breast-feeding. 

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.

You should use contraception if you could potentially become pregnant during treatment with this 
medicine.

Driving and using machines
If you use this medicine in combination with a sulphonylurea, low blood sugar (hypoglycaemia) can
occur. Hypoglycaemia may reduce your ability to concentrate. Please keep this possible problem in 
mind in all situations where you might put yourself and others at risk (e.g. driving a car or using 
machines).

Important information about some of the ingredients of Bydureon
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

3. How to use Bydureon

Always use this medicine exactly as your doctor, pharmacist, or diabetes nurse has told you. Check 
with your doctor, pharmacist, or diabetes nurse if you are not sure.

You should inject this medicine once a week, at any time of day, with or without meals.



100

You should inject this medicine into the skin (subcutaneous injection) of your stomach area 
(abdomen), upper leg (thigh), or the back of your upper arm. Do not inject into a vein or muscle.

Each week you can use the same area of your body. Be sure to choose a different injection site in that 
area.

Never mix insulin and Bydureon together in the same injection. If you need to give yourself both at the 
same time, use two separate injections. You may give both injections in the same body area (for 
example, your stomach area), but you should not give the injections next to each other.
Test your blood glucose levels regularly, it is particularly important to do this if you are also using a 
sulphonylurea.

Follow the “Instructions for the User” provided in the carton to inject Bydureon

Your doctor or diabetes nurse should teach you how to inject this medicine before you use it for the 
first time.

Check that the liquid in the syringe is clear and free of particles before you begin. After mixing, use 
the suspension only if the mixture is white to off white and cloudy. If you see clumps of dry powder 
on the sides or bottom of the vial, the medicine is NOT mixed well. Shake vigorously again until well 
mixed.

You should inject this medicine immediately after mixing the powder and the solvent.

Use a new injection needle for each injection and dispose of it safely after each use as instructed by 
your doctor or diabetes nurse. 

If you use more Bydureon than you should
If you use more of this medicine than you should, please consult with your doctor first as you may 
need medical treatment. Using too much of this medicine can cause nausea, vomiting, dizziness, or 
symptoms of low blood sugar (see section 4).

If you forget to use Bydureon
You might like to choose a day that you always plan to make your Bydureon injection. 

If you miss a dose and there are 3 days or more until your next dose is due, then take the missed dose 
as soon as it is possible to do so. For your next injection you can return to your chosen injection day. 
If you miss a dose and there are only 1 or 2 days until your next dose is due, skip the missed dose and 
take the next one as usual, on the day it is due. You can also change your chosen injection day, as long 
as your last dose was given 3 or more days before. 

Do not take two doses of Bydureon within 3 days of each other.

If you are not sure you have taken the full dose of Bydureon
If you are not sure if you have taken all of your dose, do not inject another dose of this medicine, just 
take it next week as planned.

If you stop using Bydureon
If you feel you should stop using this medicine, please consult your doctor first. If you stop using this 
medicine this can affect your blood sugar levels. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or diabetes 
nurse.



101

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Severe allergic reactions (anaphylaxis) have been reported rarely (may affect up to 1 in 1,000 
people).

You should see your doctor immediately if you experience symptoms such as
 Swelling of the face, tongue or throat (angioedema)
 Hypersensitivity (rashes, itching and rapid swelling of the tissues of the neck, face, mouth or 

throat)
 Difficulty with swallowing
 Hives and difficulty with breathing

Cases of inflammation of the pancreas (pancreatitis) have been reported uncommonly (may affect 
up to 1 in 100 people ) in patients receiving this medicine. Pancreatitis can be a serious, potentially 
life-threatening medical condition. 

 Tell your doctor if you have had pancreatitis, gallstones, alcoholism or very high triglycerides. 
These medical conditions can increase the risk of getting pancreatitis, or getting it again, 
whether or not you are taking this medicine.

 STOP taking this medicine and contact your doctor immediately if you experience severe and 
persistent stomach pain, with or without vomiting, because you could have an inflamed 
pancreas (pancreatitis).

Very common side effects (may affect more than 1 in 10 people)
 nausea (nausea is most common when first starting this medicine, but decreases over time in 

most patients) 
 diarrhoea 
 hypoglycaemia (low blood sugar) when taken with a medicine that contains a sulphonylurea.

When this medicine is used with a medicine that contains a sulphonylurea, episodes of low blood 
sugar (hypoglycaemia, generally mild to moderate) can occur. The dose of your sulphonylurea 
medicine may need to be reduced while you use this medicine. The signs and symptoms of low blood 
sugar may include headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast 
heartbeat, sweating, and feeling jittery. Your doctor should tell you how to treat low blood sugar.

Common side effects (may affect up to 1 in 10 people)
 hypoglycaemia (low blood sugar) when taken with an insulin
 dizziness
 headache
    vomiting 
 loss of energy and strength
 tiredness (fatigue) 
 constipation
 pain in the stomach area 
 bloating 
 indigestion 
 flatulence (passing gas)
 heartburn 
 reduced appetite

This medicine may reduce your appetite, the amount of food you eat, and your weight. 
If you lose weight too quickly (more than 1.5 kg per week) talk to your doctor about it since this may
cause problems such as gallstones.

 injection site reactions



102

If you have an injection site reaction (redness, rash, or itching) you may like to ask your doctor for 
something to help relieve any signs or symptoms. You may see or feel a small bump under the skin 
after your injection; it should go away after 4 to 8 weeks. You should not need to stop your treatment.

Uncommon side effects
 decrease in kidney function
 dehydration, sometimes with a decrease in kidney function
 intestinal obstruction (blockage in intestine)
 burping 
 unusual taste in the mouth
 increased sweating
 hair loss
 sleepiness

Rare side effects 
 feeling jittery

Not known (frequency cannot be estimated from the available data)
In addition some other side effects have been reported:

 bleeding or bruising more easily than normal due to low level of blood platelets.
 changes in INR (measurement of blood thinning) have been reported when used together with 

warfarin.
 skin reactions at the injection site following injection of exenatide. These include: cavity 

containing pus (abscess) and swollen, or red area of skin that feels hot and tender (cellulitis).

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or diabetes nurse. This includes any 
possible side effects not listed in this leaflet. You can also report side effects directly via the national 
reporting system listed in Appendix V. By reporting side effects, you can help provide more 
information on the safety of this medicine.

5. How to store Bydureon

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated on the label and the carton after EXP. 
The expiry date refers to the last day of that month.

Store in a refrigerator (2 °C to 8 °C). Do not freeze. 
The kit 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.
Throw away any Bydureon kit that has been frozen.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Bydureon contains
- The active substance is exenatide. Each vial contains 2 mg of exenatide. 
- The other ingredients are:
- In the powder: poly (D,L-lactide-co-glycolide) and sucrose.
- In the solvent: carmellose sodium, sodium chloride, polysorbate 20, sodium dihydrogen 

phosphate monohydrate, disodium phosphate heptahydrate and water for injection.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


103

What Bydureon looks like and contents of the pack

Powder and solvent for prolonged-release suspension for injection.

The powder is white to off-white and the solvent is a clear, colourless to pale yellow to pale brown 
solution.

Each single-dose kit consists of one vial containing 2 mg exenatide powder, one pre-filled syringe 
containing 0.65 mL solvent, one vial connector, and two injection needles. One needle is a spare. 

This medicine is available in pack sizes of 4 single-dose kits and 3 packs of 4 single-dose kits. Not all 
pack sizes may be marketed.

Marketing Authorisation Holder
AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer
AstraZeneca UK Limited
Silk Road Business Park,
Macclesfield, Cheshire, SK10 2NA
United Kingdom

Swords Laboratories T/A Lawrence Laboratories
Unit 12 Distribution Centre, Shannon Industrial Estate, Shannon, Co. Clare
Ireland

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
AstraZeneca S.A./N.V.
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 (2) 44 55 000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V.
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca 
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00

Ελλάδα Österreich



104

AstraZeneca A.E.
Τηλ: +30 210 6871500

AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0

España
AstraZeneca Farmacéutica Spain, S.A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o.
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
AstraZeneca Produtos Farmacêuticos, Lda.
Tel: +351 21 434 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z.
Tel: +421 2 5737 7777 

Italia
AstraZeneca S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the website of the European Medicines Agency 
http://www.ema.europa.eu/

http://www.emea.europa.eu/


105

Package Leaflet: Information for the user

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled 
pen

exenatide

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist, or diabetes nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist, or diabetes nurse. This includes any 

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Bydureon is and what it is used for
2. What you need to know before you use Bydureon
3. How to use Bydureon
4. Possible side effects
5. How to store Bydureon
6. Contents of the pack and other information

1. What Bydureon is and what it is used for

Bydureon contains the active substance exenatide. It is an injectable medicine used to improve blood 
sugar control in adults with type 2 diabetes mellitus.

This medicine is used in combination with the following diabetes medicines: metformin, 
sulphonylureas, thiazolidinediones, SGLT2 inhibitors and/or a long-acting insulin. Your doctor is now 
prescribing this medicine as an additional medicine to help control your blood sugar. Continue to 
follow your food and exercise plan

You have diabetes because your body does not make enough insulin to control the level of sugar in 
your blood or your body is not able to use the insulin properly. This medicine helps your body to 
increase the production of insulin when your blood sugar is high. 

2. What you need to know before you use Bydureon

Do not use Bydureon:
- If you are allergic to exenatide or any of the other ingredients of this medicine (listed in section 

6).

Warnings and precautions
Talk to your doctor, pharmacist, or diabetes nurse before using Bydureon about the following:
- If you use this medicine in combination with a sulphonylurea, as low blood sugar 

(hypoglycaemia) can occur. Test your blood glucose levels regularly. Ask your doctor, 
pharmacist, or diabetes nurse if you are not sure if any of your other medicines contain a 
sulphonylurea.

- If you have type 1 diabetes or diabetic ketoacidosis, as this medicine should not be used.
- How to inject this medicine. It should be injected into the skin and not into a vein or into the 

muscle. 



106

- If you have severe problems with your stomach emptying (including gastroparesis) or food 
digestion, as the use of this medicine is not recommended. The active substance in this medicine 
slows stomach emptying so food passes more slowly through your stomach.

- If you have ever had inflammation of the pancreas (pancreatitis) (see section 4).
- If you lose weight too quickly (more than 1.5 kg per week) talk to your doctor about it since this 

may cause problems such as gallstones.
- If you have severe kidney disease or you are on dialysis, as the use of this medicine is not 

recommended.

Bydureon is not an insulin and should therefore not be used as a substitute for insulin. 

Children and adolescents
Do not give this medicine to children and adolescents less than 18 years, as there is no experience with 
this medicine in this age group.

Other medicines and Bydureon
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines, particularly: 
− other medicines that are used to treat type 2 diabetes such as medicines that work like Bydureon 

(for example: liraglutide or other exenatide containing products), as taking these medicines with 
Bydureon is not recommended.

− medicines used to thin the blood (anticoagulants), e.g. Warfarin, as you will require additional 
monitoring of changes in INR (measurement of blood thinning) during initiation of therapy with 
this medicine.

− a medicine that contains a sulphonylurea, as low blood sugar (hypoglycaemia) can occur when 
combined with Bydureon. 

− if you are using insulin, your doctor will tell you how to reduce the dose of insulin and will 
recommend that you monitor your blood sugar more frequently, in order to avoid hyperglycaemia 
(high blood sugar) and diabetic ketoacidosis (a complication of diabetes that occurs when the body 
is unable to break down glucose because there is not enough insulin).

Pregnancy and breast-feeding
It is not known if this medicine may harm your unborn child, therefore you should not use it during 
pregnancy and for at least 3 months before a planned pregnancy.

It is not known if exenatide passes into your milk. You should not use this medicine while 
breast-feeding.

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.

You should use contraception if you could potentially become pregnant during treatment with this 
medicine.

Driving and using machines
If you use this medicine in combination with a sulphonylurea, low blood sugar (hypoglycaemia) can
occur. Hypoglycaemia may reduce your ability to concentrate. Please keep this possible problem in 
mind in all situations where you might put yourself and others at risk (e.g. driving a car or using 
machines).

Important information about some of the ingredients of Bydureon
This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”. 



107

3. How to use Bydureon 

Always use this medicine exactly as your doctor, pharmacist, or diabetes nurse has told you. Check 
with your doctor, pharmacist, or diabetes nurse if you are not sure.

You should inject this medicine once a week, at any time of day, with or without meals.

You should inject this medicine into the skin (subcutaneous injection) of your stomach area 
(abdomen), upper leg (thigh), or the back of your upper arm. Do not inject into a vein or muscle.

Each week you can use the same area of your body. Be sure to choose a different injection site in that 
area.

Never mix insulin and Bydureon together in the same injection. If you need to give yourself both at the 
same time, use two separate injections. You may give both injections in the same body area (for 
example, your stomach area), but you should not give the injections next to each other.

Test your blood glucose levels regularly, it is particularly important to do this if you are also using a 
sulphonylurea.

Follow the “Instructions for the User” provided in the carton to inject Bydureon

Your doctor or diabetes nurse should teach you how to inject this medicine before you use it for the 
first time.

Remove one pen from the refrigerator and let it stand at room temperature for at least 15 minutes.
Check that the liquid in the pen is clear and free of particles before you begin. After mixing the liquid 
with the powder, use the suspension only if the mixture is white to off white and cloudy. If you see 
clumps of dry powder on the sides of the pen, the medicine is NOT mixed well. Tap vigorously again 
until well mixed.

You should inject this medicine immediately after mixing the powder and the solvent.

Use a new pen for each injection. You should dispose of the pen safely, with the needle still attached, 
after use, as instructed by your doctor or diabetes nurse.

If you use more Bydureon than you should
If you use more of this medicine than you should, please consult with your doctor first as you may 
need medical treatment. Using too much of this medicine can cause nausea, vomiting, dizziness, or 
symptoms of low blood sugar (see section 4).

If you forget to use Bydureon 
You might like to choose a day that you always plan to make your Bydureon injection. 

If you miss a dose and there are 3 days or more until your next dose is due, then take the missed dose 
as soon as it is possible to do so. For your next injection you can return to your chosen injection day.  
If you miss a dose and there are only 1 or 2 days until your next dose is due, skip the missed dose and 
take the next one as usual, on the day it is due. You can also change your chosen injection day, as long 
as your last dose was given 3 or more days before. 

Do not take two doses of Bydureon within 3 days of each other.

If you are not sure you have taken the full dose of Bydureon
If you are not sure if you have taken all of your dose, do not inject another dose of this medicine, just 
take it next week as planned.



108

If you stop using Bydureon 
If you feel you should stop using this medicine, please consult your doctor first. If you stop using this 
medicine this can affect your blood sugar levels. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or diabetes 
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Severe allergic reactions (anaphylaxis) have been reported rarely (may affect up to 1 in 1,000 
people).

You should see your doctor immediately if you experience symptoms such as
 Swelling of the face, tongue or throat (angioedema) 
 Hypersensitivity (rashes, itching and rapid swelling of the tissues of the neck, face, mouth or 

throat)
 Difficulty with swallowing
 Hives and difficulty with breathing

Cases of inflammation of the pancreas (pancreatitis) have been reported uncommonly ( may affect 
up to 1 in 100 people) in patients receiving this medicine. Pancreatitis can be a serious, potentially 
life-threatening medical condition. 

 Tell your doctor if you have had pancreatitis, gallstones, alcoholism or very high triglycerides. 
These medical conditions can increase the risk of getting pancreatitis, or getting it again, 
whether or not you are taking this medicine.

 STOP taking this medicine and contact your doctor immediately if you experience severe and 
persistent stomach pain, with or without vomiting, because you could have an inflamed 
pancreas (pancreatitis).

Very common side effects (may affect more than 1 in 10 people)
 nausea (nausea is most common when first starting this medicine, but decreases over time in 

most patients) 
 diarrhoea 
 hypoglycaemia (low blood sugar) when taken with a medicine that contains a sulphonylurea

When this medicine is used with a medicine that contains a sulphonylurea, episodes of low blood 
sugar (hypoglycaemia, generally mild to moderate) can occur. The dose of your sulphonylurea 
medicine may need to be reduced while you use this medicine. The signs and symptoms of low blood 
sugar may include headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast 
heartbeat, sweating, and feeling jittery. Your doctor should tell you how to treat low blood sugar.

Common side effects (may affect up to 1 in 10 people)
 hypoglycaemia (low blood sugar) when taken with an insulin
 dizziness 
 headache 
 vomiting
 loss of energy and strength
 tiredness (fatigue) 
 constipation
 pain in the stomach area 
 bloating 
 indigestion 
 flatulence (passing gas)



109

 heartburn 
 reduced appetite

This medicine may reduce your appetite, the amount of food you eat, and your weight. 
If you lose weight too quickly (more than 1.5 kg per week) talk to your doctor about it since this may 
cause problems such as gallstones.

 injection site reactions
If you have an injection site reaction (redness, rash, or itching) you may like to ask your doctor for 
something to help relieve any signs or symptoms. You may see or feel a small bump under the skin 
after your injection; it should go away after 4 to 8 weeks. You should not need to stop your treatment.

Uncommon side effects 
 decrease in kidney function
 dehydration, sometimes with a decrease in kidney function
 intestinal obstruction (blockage in intestine)
 burping 
 unusual taste in the mouth
 increased sweating
 hair loss
 sleepiness

Rare side effects
 feeling jittery

Not known (frequency cannot be estimated from the available data)
In addition some other side effects have been reported:

 bleeding or bruising more easily than normal due to low level of blood platelets. 
 changes in INR (measurement of blood thinning) have been reported when used together with 

warfarin.
 skin reactions at the injection site following injection of exenatide. These include: cavity 

containing pus (abscess) and swollen, or red area of skin that feels hot and tender (cellulitis).

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or diabetes nurse. This includes any 
possible side effects not listed in this leaflet. You can also report side effects directly via the national 
reporting system listed in Appendix V. By reporting side effects, you can help provide more 
information on the safety of this medicine.

5. How to store Bydureon

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated on the label and the carton after EXP. 
The expiry date refers to the last day of that month.

Store in a refrigerator (2 °C to 8 °C). Do not freeze. 
The pen 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. 
Throw away any Bydureon pen that has been frozen.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


110

6. Contents of the pack and other information

What Bydureon contains
- The active substance is exenatide. Each pre-filled pen contains 2 mg of exenatide. After 

suspension, the delivered dose is 2 mg/0.65 mL.
- The other ingredients are:
- In the powder: poly (D,L-lactide-co-glycolide) and sucrose.
- In the solvent: carmellose sodium, sodium chloride, polysorbate 20, sodium dihydrogen 

phosphate monohydrate, disodium phosphate heptahydrate, water for injection and sodium 
hydroxide (for pH adjustment).

What Bydureon looks like and contents of the pack

This medicine is provided as a powder and solvent (liquid) for suspension for injection in a pre-filled 
pen. The powder (2 mg) in one chamber, is white to off-white and the solvent (0.65 mL) in the other 
chamber, is a clear, colourless to pale yellow to pale brown solution. Each single-dose pre-filled pen is 
provided with one custom needle. Each carton also contains one spare needle.

This medicine is available in pack of 4 single-dose pre-filled pens, and a multipack containing 12 (3 
packs of 4) single-dose pre-filled pens. Not all pack sizes may be marketed.

Marketing Authorisation Holder
AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer
AstraZeneca AB
Gärtunavägen
SE-151 85 Södertälje
Sweden

AstraZeneca UK Limited
Silk Road Business Park,
Macclesfield, Cheshire, SK10 2NA
United Kingdom

Swords Laboratories T/A Lawrence Laboratories
Unit 12 Distribution Centre, Shannon Industrial Estate, Shannon, Co. Clare
Ireland

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
AstraZeneca S.A./N.V.
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 (2) 44 55 000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V.
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500



111

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca 
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00

Ελλάδα
AstraZeneca A.E.
Τηλ: +30 210 6871500

Österreich
AstraZeneca Österreich GmbH
Tel: +43 1 711 31 0

España
AstraZeneca Farmacéutica Spain, S.A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o.
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
AstraZeneca Produtos Farmacêuticos, Lda.
Tel: +351 21 434 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z.
Tel: +421 2 5737 7777 

Italia
AstraZeneca S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the website of the European Medicines Agency 
http://www.ema.europa.eu/

http://www.emea.europa.eu/


112

Package Leaflet: Information for the user

Bydureon 2 mg prolonged-release suspension for injection in pre-filled pen
exenatide

Read all of this leaflet carefully before you start using this medicine because it contains 
important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist, or diabetes nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist, or diabetes nurse. This includes any 

possible side effects not listed in this leaflet. See section 4.

What is in this leaflet

1. What Bydureon is and what it is used for
2. What you need to know before you use Bydureon 
3. How to use Bydureon 
4. Possible side effects
5. How to store Bydureon
6. Contents of the pack and other information

1. What Bydureon is and what it is used for

Bydureon contains the active substance exenatide. It is an injectable medicine used to improve blood 
sugar control in adults with type 2 diabetes mellitus.

This medicine is used in combination with the following diabetes medicines: metformin, 
sulphonylureas, thiazolidinediones, SGLT2 inhibitors and/or a long-acting insulin. Your doctor is now 
prescribing this medicine as an additional medicine to help control your blood sugar. Continue to 
follow your food and exercise plan.

You have diabetes because your body does not make enough insulin to control the level of sugar in 
your blood or your body is not able to use the insulin properly. This medicine helps your body to 
increase the production of insulin when your blood sugar is high. 

2. What you need to know before you use Bydureon 

Do not use Bydureon:
- If you are allergic to exenatide or any of the other ingredients of this medicine (listed in section 

6).

Warnings and precautions
Talk to your doctor, pharmacist, or diabetes nurse before using Bydureon about the following:
- If you use this medicine in combination with a sulphonylurea, as low blood sugar 

(hypoglycaemia) can occur. Test your blood glucose levels regularly. Ask your doctor, 
pharmacist, or diabetes nurse if you are not sure if any of your other medicines contain a 
sulphonylurea.

- If you have type 1 diabetes or diabetic ketoacidosis, as this medicine should not be used.
- How to inject this medicine. It should be injected into the skin and not into a vein or into the 

muscle. 
- If you have severe problems with your stomach emptying (including gastroparesis) or food 

digestion, as the use of this medicine is not recommended. The active substance in this medicine 
slows stomach emptying so food passes more slowly through your stomach.



113

- If you have ever had inflammation of the pancreas (pancreatitis) (see section 4).
- If you lose weight too quickly (more than 1.5 kg per week) talk to your doctor about it since this 

may cause problems such as gallstones.
- If you have severe kidney disease or you are on dialysis, as the use of this medicine is not 

recommended.

Bydureon is not an insulin and should therefore not be used as a substitute for insulin. 

Children and adolescents
Do not give this medicine to children and adolescents less than 18 years, as there is no experience with 
this medicine in this age group.

Other medicines and Bydureon
Tell your doctor or pharmacist if you are taking, have recently taken, or might take any other 
medicines, particularly:
- other medicines that are used to treat type 2 diabetes, such as medicines that work like 

Bydureon (for example: liraglutide or other exenatide containing products, as taking these 
medicines with Bydureon is not recommended.

- medicines used to thin the blood (anticoagulants), e.g. Warfarin, as you will require additional 
monitoring of changes in INR (measurement of blood thinning) during initiation of therapy with 
this medicine.

- a medicine that contains a sulphonylurea, as low blood sugar (hypoglycaemia) can occur when 
combined with Bydureon.

- if you are using insulin, your doctor will tell you how to reduce the dose of insulin and will 
recommend that you monitor your blood sugar more frequently, in order to avoid 
hyperglycaemia (high blood sugar) and diabetic ketoacidosis (a complication of diabetes that 
occurs when the body is unable to break down glucose because there is not enough insulin).

Pregnancy and breast-feeding
It is not known if this medicine may harm your unborn child, therefore you should not use it during 
pregnancy and for at least 3 months before a planned pregnancy.

It is not known if exenatide passes into your milk. You should not use this medicine while 
breast-feeding. 

If you are pregnant or breast-feeding, think you may be pregnant, or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine.

You should use contraception if you could potentially become pregnant during treatment with this 
medicine.

Driving and using machines
If you use this medicine in combination with a sulphonylurea, low blood sugar (hypoglycaemia) can
occur. Hypoglycaemia may reduce your ability to concentrate. Please keep this possible problem in 
mind in all situations where you might put yourself and others at risk (e.g. driving a car or using 
machines).

3. How to use Bydureon

BCise is the name of the pre-filled pen device used to inject your Bydureon medicine. 

Always use this medicine exactly as your doctor, pharmacist, or diabetes nurse has told you. Check 
with your doctor, pharmacist, or diabetes nurse if you are not sure.

You should inject this medicine once a week, at any time of day, with or without meals.



114

You should inject this medicine into the skin (subcutaneous injection) of your stomach area 
(abdomen), upper leg (thigh), or the back of your upper arm. Do not inject into a vein or muscle. 

Each week you can use the same area of your body. Be sure to choose a different injection site in that 
area.

Test your blood glucose levels regularly, it is particularly important to do this if you are also using a 
sulphonylurea.

Follow the “Instructions for the User” provided in the carton to inject Bydureon BCise

Your doctor or diabetes nurse should teach you how to inject this medicine before you use it for the 
first time.

Remove one pen from the refrigerator and rest it flat for at least 15 minutes. Mix the suspension by 
shaking hard for at least 15 seconds. Use the suspension only if it is evenly mixed, white to off-white 
and cloudy. If you see white medicine on the sides, bottom or top of the pen window, the medicine is 
NOT mixed well. Shake hard again until well mixed.

You should inject this medicine immediately after mixing the suspension.

Use a new pen for each injection. You should dispose of the pen safely after each use, as instructed by 
your doctor or diabetes nurse. 

If you use more Bydureon than you should
If you use more of this medicine than you should, please consult your doctor first as you may need 
medical treatment. Using too much of this medicine can cause nausea, vomiting, dizziness, or 
symptoms of low blood sugar (see section 4).

If you forget to use Bydureon
You might like to choose a day that you always plan to make your Bydureon injection. 

If you miss a dose and there are 3 days or more until your next dose is due, then take the missed dose 
as soon as it is possible to do so. For your next injection you can return to your chosen injection day. 
If you miss a dose and there are only 1 or 2 days until your next dose is due, skip the missed dose and 
take the next one as usual, on the day it is due. You can also change your chosen injection day, as long 
as your last dose was given 3 or more days before. 

Do not take two doses of Bydureon within 3 days of each other.

If you are not sure you have taken the full dose of Bydureon
If you are not sure if you have taken all of your dose, do not inject another dose of this medicine, just 
take it next week as planned.

If you stop using Bydureon
If you feel you should stop using this medicine, please consult your doctor first. If you stop using this 
medicine this can affect your blood sugar levels. 

If you have any further questions on the use of this medicine, ask your doctor, pharmacist, or diabetes 
nurse.

4. Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.



115

Severe allergic reactions (anaphylaxis) have been reported rarely (may affect up to 1 in 1,000 
people).

You should see your doctor immediately if you experience symptoms such as
 Swelling of the face, tongue or throat (angioedema)
 Hypersensitivity (rashes, itching and rapid swelling of the tissues of the neck, face, mouth or 

throat)
 Difficulty with swallowing
 Hives and difficulty with breathing

Cases of inflammation of the pancreas (pancreatitis) have been reported uncommonly (may affect 
up to 1 in 100 people) in patients receiving this medicine. Pancreatitis can be a serious, potentially 
life-threatening medical condition. 

 Tell your doctor if you have had pancreatitis, gallstones, alcoholism or very high triglycerides. 
These medical conditions can increase the risk of getting pancreatitis, or getting it again, 
whether or not you are taking this medicine.

 STOP taking this medicine and contact your doctor immediately if you experience severe and 
persistent stomach pain, with or without vomiting, because you could have an inflamed 
pancreas (pancreatitis).

Very common side effects (may affect more than 1 in 10 people)
 hypoglycaemia (low blood sugar) when taken with a medicine that contains a sulphonylurea

When this medicine is used with a medicine that contains a sulphonylurea, episodes of low blood 
sugar (hypoglycaemia, generally mild to moderate) can occur. The dose of your sulphonylurea 
medicine may need to be reduced while you use this medicine. The signs and symptoms of low blood 
sugar may include headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast 
heartbeat, sweating, and feeling jittery. Your doctor should tell you how to treat low blood sugar.

Common side effects (may affect up to 1 in 10 people)
 hypoglycaemia (low blood sugar) when taken with an insulin
 headache
 dizziness
 nausea (nausea is most common when starting this medicine, but decreases over time in most 

patients)
 diarrhoea
 vomiting 
 constipation
 indigestion
 heartburn
 bloating
 pain in the stomach area
 injection site itchiness or redness
 tiredness (fatigue) 

Uncommon side effects 
 hypoglycaemia (low blood sugar) when this medicine is used with a medicine that does not 

contain a sulphonylurea
 reduced appetite

This medicine may reduce your appetite, the amount of food you eat, and your weight. 
If you lose weight too quickly (more than 1.5 kg per week) talk to your doctor about it since this may
cause problems such as gallstones.

 dehydration
 unusual taste in the mouth



116

 sleepiness
 flatulence (passing gas)
 burping
 intestinal obstruction (blockage in intestine)
 hives 
 increased sweating
 rash, itching
 hair loss
 decrease in kidney function
 injection site reactions

If you have an injection site reaction (redness, rash, or itching) you may like to ask your doctor for 
something to help relieve any signs or symptoms. You may see or feel a small bump under the skin 
after your injection; it should go away after 4 to 8 weeks. You should not need to stop your treatment.

 loss of energy and strength

Rare side effects 
 feeling jittery

Not known (frequency cannot be estimated from the available data)
In addition some other side effects have been reported:

 bleeding or bruising more easily than normal due to low level of blood platelets. 
 skin reactions at the injection site following injection of exenatide. These include: cavity 

containing pus (abscess) and swollen, or red area of skin that feels hot and tender (cellulitis).
 changes in INR (measurement of blood thinning) have been reported when used together with 

warfarin.

Reporting of side effects
If you get any side effects, talk to your doctor, pharmacist or diabetes nurse. This includes any 
possible side effects not listed in this leaflet. You can also report side effects directly via the national 
reporting system listed in Appendix V. By reporting side effects, you can help provide more 
information on the safety of this medicine.

5. How to store Bydureon

Keep this medicine out of the sight and reach of children.

Do not use this medicine after the expiry date, which is stated on the label and the carton after EXP. 
The expiry date refers to the last day of that month.

Bydureon BCise pen should be stored as follows:
 Store in a refrigerator (2 °C to 8 °C). 
 The pen 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 pen must be stored flat.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment.

6. Contents of the pack and other information

What Bydureon BCise pen contains
- The active substance is exenatide. Each pre-filled pen contains 2 mg of exenatide. 
- The other ingredients are: poly (D,L-lactide-co-glycolide), sucrose and medium chain 

triglyceride.

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


117

What Bydureon looks like and contents of the pack

Prolonged-release suspension for injection in pre-filled pen (BCise).

White to off-white opaque suspension.

Each pre-filled pen delivers 2 mg of exenatide in a volume of 0.85 mL. 

This medicine is available in a pack size of 4 single-dose pre-filled pens (BCise) and a multipack 
containing 12 (3 packs of 4) single-dose pre-filled pens (BCise). Not all pack sizes may be marketed.

Marketing Authorisation Holder
AstraZeneca AB
SE-151 85 Södertälje
Sweden

Manufacturer
AstraZeneca AB
Gärtunavägen
SE-151 85 Södertälje
Sweden

AstraZeneca UK Limited
Silk Road Business Park,
Macclesfield, Cheshire, SK10 2NA
United Kingdom

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder:

België/Belgique/Belgien
AstraZeneca S.A./N.V.
Tel: +32 2 370 48 11

Lietuva
UAB AstraZeneca Lietuva
Tel: +370 5 2660550

България
АстраЗенека България ЕООД
Тел.: +359 (2) 44 55 000

Luxembourg/Luxemburg
AstraZeneca S.A./N.V.
Tél/Tel: +32 2 370 48 11

Česká republika
AstraZeneca Czech Republic s.r.o.
Tel: +420 222 807 111

Magyarország
AstraZeneca Kft.
Tel.: +36 1 883 6500

Danmark
AstraZeneca A/S
Tlf: +45 43 66 64 62

Malta
Associated Drug Co. Ltd
Tel: +356 2277 8000

Deutschland
AstraZeneca GmbH
Tel: +49 41 03 7080

Nederland
AstraZeneca BV
Tel: +31 79 363 2222

Eesti
AstraZeneca 
Tel: +372 6549 600

Norge
AstraZeneca AS
Tlf: +47 21 00 64 00

Ελλάδα
AstraZeneca A.E.

Österreich
AstraZeneca Österreich GmbH



118

Τηλ: +30 210 6871500 Tel: +43 1 711 31 0

España
AstraZeneca Farmacéutica Spain, S.A.
Tel: +34 91 301 91 00

Polska
AstraZeneca Pharma Poland Sp. z o.o.
Tel.: +48 22 245 73 00

France
AstraZeneca
Tél: +33 1 41 29 40 00

Portugal
AstraZeneca Produtos Farmacêuticos, Lda.
Tel: +351 21 434 61 00

Hrvatska 
AstraZeneca d.o.o.
Tel: +385 1 4628 000

România
AstraZeneca Pharma SRL
Tel: +40 21 317 60 41

Ireland
AstraZeneca Pharmaceuticals (Ireland) DAC
Tel: +353 1609 7100

Slovenija
AstraZeneca UK Limited
Tel: +386 1 51 35 600

Ísland
Vistor hf.
Sími: +354 535 7000

Slovenská republika
AstraZeneca AB, o.z.
Tel: +421 2 5737 7777 

Italia
AstraZeneca S.p.A.
Tel: +39 02 9801 1

Suomi/Finland
AstraZeneca Oy
Puh/Tel: +358 10 23 010

Κύπρος
Αλέκτωρ Φαρµακευτική Λτδ
Τηλ: +357 22490305

Sverige
AstraZeneca AB
Tel: +46 8 553 26 000

Latvija
SIA AstraZeneca Latvija
Tel: +371 67377100

United Kingdom
AstraZeneca UK Ltd
Tel: +44 1582 836 836

This leaflet was last revised in

Other sources of information

Detailed information on this medicine is available on the website of the European Medicines Agency 
http://www.ema.europa.eu/

http://www.emea.europa.eu/


119

INSTRUCTIONS FOR THE USER

Your step by step guide

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection

If you have questions about taking Bydureon

 Refer to the Common questions and answers

Helpful hints

 Take your time.
 Follow these instructions step by step.
 You will need enough time to complete all the steps without stopping.
 You will probably need less time as you get used to giving yourself injections.

IMPORTANT:

Read and follow each step in these instructions carefully every time you take Bydureon. Do not 
skip steps. Also read the Package Leaflet in your carton.

Your guide to the parts

Single-dose kit

Lift here for a closer look at the parts

Keep this flap open so you can refer to it as you go through the steps

Your guide to the parts

Syringe
Plunger

Liquid          
(solvent) inside White Cap

Vial

Green cap

The powder inside 
is your medicine

Blue cap Needle Needle Cover

Vial connector

Dose Line

Paper cover

Vial connector 
package

Orange connector

Needle (monoject)
The single-dose kit has a spare needle 
(not shown) in case you need it.



120

Single-dose kit

What’s inside

To take the correct dose, read each section so that you do every step in order.

This guide is divided into sections:

1 Getting started
2 Connecting the parts
3 Mixing the medicine and filling the syringe
4 Injecting the medicine

Common questions and answers.

1. Getting Started

1a Take a single-dose kit from the refrigerator. 

Prepare to safely dispose of used needles and syringes. Have what you need ready in order to safely 
dispose of used needles and syringes.

1b Wash your hands.

1c

Peel back the cover to open.

Remove the syringe. The liquid in the syringe should be clear and free of particles. It is okay if there 
are air bubbles.

Place the needle, vial connector package, vial, and syringe on a clean, flat surface.

Syringe Needles (2)

Vial Vial connector



121

Pick up the needle, and twist off the blue cap.

Put the covered needle down. The needle is now prepared. You will need it later.

There is a spare needle in case you need it.

Pick up the vial.

Tap the vial several times against a hard surface to loosen the powder.

Use your thumb to remove the green cap.

Put the vial down.

1d

Tap!

1e

1f



122

2. Connecting the parts

Pick up the vial connector package and peel off the paper cover. Do not touch the orange 
connector inside.

Hold the vial connector package.
In your other hand, hold the vial. 

2a

2b

2c



123

Press the top of the vial firmly into the orange connector.

Lift the vial with the orange connector now attached out of its package.

This is what the vial should now look like.

Put it down for later.

Pick up the syringe.

2e

2f

2d



124

With your other hand, firmly hold the 2 grey squares on the white cap.

Break off the cap

Be careful not to push in the plunger.

Just like you might break a stick, you are breaking off the cap.

This is what the broken-off cap looks like.

You will not need the cap and can throw it away.

2h

2i

2g Snap!



125

This is what the syringe should now look like.

Now, pick up the vial with the orange connector attached.

Twist the orange connector onto the syringe until snug. While twisting, be sure to hold the orange 
connector. Do not over tighten. Be careful not to push in the plunger.

This is how the parts should now look when they are connected.

3. Mixing the medicine and filling the syringe

IMPORTANT:

During these next steps, you will be mixing the medicine and filling the syringe. Once you mix 
the medicine, you must inject it immediately. You must not save the mixed medicine to inject at 
a later time. 

With your thumb, push down the plunger until it stops and hold your thumb in place.

2j

2k

3a



126

The plunger may feel like it is springing back a little.

Keep pushing down on the plunger with your thumb and shake vigorously. Keep shaking until 
the liquid and powder are mixed well. 

Do not worry that the vial might come off. The orange connector will keep it attached to the syringe.

Shake vigorously like you would shake a bottle of oil-and-vinegar salad dressing.

When the medicine is mixed well, it should look cloudy.

3b

3c



127

If you see clumps of dry powder on the sides or bottom of the vial, the medicine is NOT mixed 
well.

Shake vigorously again until well mixed.

Keep pushing on the plunger with your thumb while shaking.

Now, hold the vial so the syringe is pointing up. Keep pushing on the plunger with your thumb 
until it stops, and hold it in place.

Gently tap the vial with the other hand. Keep pushing on the plunger with your thumb to keep 
the plunger in place.

The tapping helps the medicine drip down along the sides of the vial. It is okay if there are air bubbles. 

Pull the plunger down beyond the black dashed Dose Line.

This draws the medicine from the vial into the syringe. You may see air bubbles. This is normal.

A little bit of liquid may cling to the sides of the vial. This is also normal.

3e

3f

3g



128

With one hand, hold the plunger in place so it does not move.

With the other hand, twist the orange connector to remove.

After removing the connector be careful not to push in the plunger.

This is what the syringe should now look like.

4. Injecting the medicine

IMPORTANT:

Read the next steps carefully and look closely at the pictures.
This helps you get the correct dose of medicine.

3h

3i

3j



129

Twist the needle onto the syringe until snug. Do not remove the needle cover yet.
Be careful not to push in the plunger.

Slowly push in the plunger so the top of the plunger lines up with the black dashed Dose Line.
Then, take your thumb off the plunger.

It is important to stop pushing at this point, or you will waste your medicine and you will not get the 
correct dose.

The top of the plunger must stay lined up with the black dashed Dose Line as you go through the 
next steps. This will help you get the correct dose of medicine.

IMPORTANT:

It is normal to see a few air bubbles in the mixture.
The air bubbles will not harm you or affect your dose.

4a

Slowly 
push

Top of 
plunger

4b

4c



130

You can inject each dose of the medicine in your stomach area (abdomen), your thigh, or the 
back of your upper arm.

Each week you can use the same area of your body. But be sure to choose a different injection site in 
that area.

Hold the syringe near the black dashed Dose Line.

Pull the needle cover straight off.
Do not twist.

Be careful not to push in the plunger.

When you remove the cover, you may see 1 or 2 drops of liquid. This is normal.

Back of 

upper arm

Stomach

Thigh

Front Back

Areas on body for injection

4d

4e

Pull

4f



131

Be sure to use the injection technique recommended by your doctor or diabetes nurse.
Remember: You must take your injection of Bydureon immediately after mixing it.

Insert the needle into your skin (subcutaneously). To inject your full dose, push down on the 
plunger with your thumb until it stops.

Withdraw the needle.

Refer to the package leaflet (section 3) on what to do if you are not sure if you have received a 
complete dose.

4h. Dispose of the syringe with the needle still attached as instructed by your doctor or diabetes 
nurse. DO NOT try to recap or reuse the needle.
You do not have to save any parts. Each single-dose kit has everything you need for your weekly dose 
of Bydureon.

Medicines should not be disposed of via waste water or household waste. Ask your pharmacist how to 
dispose of medicines no longer required. These measures will help to protect the environment.

When it is time for your next weekly dose, start again at step 1.

Common questions and answers

If your question is about:                           See question number:
How soon to inject after mixing 1
Mixing the medicine 2
Air bubbles in syringe 3
Attaching the needle 4
Removing the needle cover 5
Plunger not lining up with black dashed Dose Line 6
Being unable to push the plunger down when injecting 7

Common questions and answers

1. After I mix the medicine, how long can I wait before taking the injection?

You must take your injection of Bydureon immediately after mixing it. If you do not inject Bydureon 
immediately, the medicine will start to form small clumps in the syringe. These clumps could clog the 
needle when you take the injection (see question 7).

2. How do I know that the medicine is mixed well?

When the medicine is mixed well, it should look cloudy. There should not be any dry powder on the 
sides or bottom of the vial. If you do see any dry powder, shake vigorously while continuing to push 
down on the plunger with your thumb. (This question relates to the steps shown in sections 3a to 3d).

4g



132

3. I’m ready to take the injection. What should I do if I see air bubbles in the syringe?

It is normal for air bubbles to be in the syringe. The air bubbles will not harm you or affect your dose. 
Bydureon is injected into your skin (subcutaneously). Air bubbles are not a problem with this type of 
injection.

4. What should I do if I have trouble attaching the needle?

First, be sure you have removed the blue cap. Then, twist the needle onto the syringe until snug. To 
prevent losing medicine, do not push in the plunger while attaching the needle. For more information 
on injection techniques talk with your health care professional.
(This question relates to step 4a.)

5. What should I do if I have trouble removing the needle cover?

With one hand, hold the syringe near the black dashed Dose Line. With your other hand, hold the 
needle cover. Pull the needle cover straight off. Do not twist it. (This question relates to step 4f.)

6. I am at step 4c. What should I do if the top of the plunger has been pushed past the black 
dashed Dose Line?

The black dashed Dose Line shows the correct dose. If the top of the plunger has been pushed past the 
line, you should continue from step 4d and take the injection. Before your next injection in 1 week, 
carefully review the instructions for steps 3a to 4h. 

7. When I inject, what should I do if I cannot push the plunger all the way down?

This means the needle has become clogged. Remove the needle and replace it with the spare needle 
from your kit. Then choose a different injection site and finish taking the injection.

To review how to:
 Remove the blue cap of the needle, see step 1d 
 Attach the needle, see step 4a 
 Remove the needle cover and give the injection, see steps 4e to 4g

If you still cannot push the plunger all the way down, withdraw the needle. Refer to the package leaflet 
(section 3) on what to do if you are not sure if you have received a complete dose.

To prevent a clogged needle, always mix the medicine very well, and inject immediately after mixing.

Bydureon only needs to be taken once a week.

Make a note that you have taken your Bydureon today and mark your calendar for when you are due 
for your next injection.

Where to learn more about Bydureon

 Talk with your doctor, pharmacist or diabetes nurse
 Read the Package Leaflet carefully



133

INSTRUCTIONS FOR THE USER 
Read these instructions carefully before use

Bydureon 2 mg powder and solvent for prolonged-release suspension for injection in pre-filled 
pen

How to use Bydureon pre-filled pen 

Cover

Knob

Orange Label

Striped Label

Needle Top of pen

Mixing window

Inspection window
Green label

Prior to use of the pen, it is recommended that you should be trained by a doctor or diabetes nurse on 

its proper use.

Unless a trained person can help to inject this medicine it is not recommended for people who are 

blind or cannot see well.

Step 1: Prepare your pen

A. Let your pen warm up. 

Remove one pen from the refrigerator and 

let it stand at room temperature for at least 

15 minutes. DO NOT use a pen past its 

expiration date.

WAIT
15

Minutes

Wash your hands while the pen is warming up.

B. Open the tray, 

by pulling on the corner tab. Then remove 

the pen and needle. DO NOT use your pen 

or needle if any parts are broken or 

missing.

C. Check the liquid, 

inside the inspection window. It should be 

clear and free of particles. It’s normal if 

you see air bubbles in the liquid.

D. Peel off the paper tab, 

from the needle cover.



134

E. Attach the needle to the pen,

by pushing and screwing it onto the top of 

the pen until it is tight. DO NOT remove 

the needle cover yet.

DO NOT proceed unless needle is attached

Step 2: Mix your dose

A. Combine the medicine.

While holding the pen upright with the 

needle cover uppermost, slowly turn the 

knob anticlockwise. STOP when you hear 

the click and the green label disappears.

B. Firmly tap the pen to mix.

 Hold the pen by the end with the orange 

label and tap the pen firmly against the 

palm of your hand.

 WITHOUT twisting the knob, ROTATE

the pen every few taps. 

 Tap the prefilled pen firmly until a 

uniformly cloudy suspension with no 

clumps is obtained. 

 You may need to tap 80 times or more.

C. Check the suspension. 

Hold the pen up to the light and look through both sides of the mixing window. The 

solution should have NO CLUMPS and be uniformly cloudy.

80 times or more

Hold Upright

CLICK!



135

To get your full dose the medicine must be mixed well.

If it’s not mixed well, tap longer and more firmly.

DO NOT proceed unless your medicine is mixed well

To get your full dose the medicine must be mixed well. If it’s not mixed well, tap longer and more 

firmly. It’s normal if you see air bubbles in the liquid, and they will cause no harm.

D. Compare both sides of the mixing window to the photos below, 

by holding the pen against the page. Pay attention to the bottom surface. If you don’t see 

clumps you are ready to inject.

Step 3: Inject your dose

IMPORTANT Once the medicine is mixed well, you must inject the dose immediately. You 

cannot save it for later use.

A. Choose your injection site,

in either your stomach, thigh, or back of the 

arm. Each week you can use the same area 

of your body but choose a different 

injection site in that area. Gently clean the 

area with soap and water or an alcohol 

swab. 



136

B. Twist knob to release injection button.

While holding the pen upright with the 

needle cover uppermost, twist the knob 

anticlockwise until the orange label 

disappears and the injection button is 

released. DO NOT push the injection 

button yet.

C. Remove the needle cover,

by pulling straight off. DO NOT twist. You 

may see a few drops of liquid on the needle 

or in the cover.

D. Inject the medicine. 

Insert the needle into your skin 

(subcutaneously). Press the injection button 

with your thumb until you hear a click. 

Hold for 10 seconds to make sure you get 

the full dose.

E. Properly dispose of your pen, 

with the needle attached, in a 

puncture-resistant container. DO NOT try 

to recap or reuse the needle.

Common Questions and Answers

1. How do I know that the medicine is mixed well?

The medicine is mixed well when the liquid looks cloudy from both sides of the window. You 

should not see any clumps in the liquid. It may help to hold the pen up to the light to see in the 

window. If you see clumps of any size keep tapping the pen firmly against the palm of your 

hand until mixed.

2. I am having trouble mixing my dose. What should I do?

Remember, before preparing your dose, leave the pen out of the refrigerator for at least 15 

minutes. This will let the pen warm up to room temperature. It will be easier to mix the 

medicine if the pen is at room temperature.

Be sure you are holding the pen at the end with the knob and the orange label. This will help 

you grip the pen better and tap it more firmly against your palm.

It may also help to tap the mixing window on both sides against your palm. If you see any 

clumps, keep tapping.

Hold 
Upright

Injection 
Button



137

3. After I mix the medicine, how long can I wait before taking the injection?

You must inject your dose right after mixing it. If you do not inject your dose right away, 

small clumps of medicine may form in the pen and you may not get your full dose.

4. I’m ready to inject my dose. What should I do if I see air bubbles in the pen?

It is normal for air bubbles to be in the pen. The medicine is injected into your skin 

(subcutaneously). Air bubbles will not harm you or affect your dose with this type of 

injection.

5. What should I do if I cannot push the injection button all the way in when trying to 

inject my dose?

Check that you have fully screwed on the pen needle. Also be sure you twisted the knob until 

it stopped, the orange label disappeared, and the injection button appears.

If you still cannot push the button in, this may mean that the needle is clogged. Remove the 

needle from your skin and replace it with the spare needle from the carton. Review how to 

attach the needle. Then choose a different injection site and finish taking the injection.

If you still cannot push the button all the way in, remove the needle from your skin. Use a 

puncture-resistant container to throw away the pen with the needle still attached.

6. How do I know if I injected my full dose?

To be sure you get your full dose, press the injection button with your thumb until you hear a 

click. After the click, continue to hold the needle in your skin for 10 seconds. This will allow 

enough time for all the medicine to go from the pen to under your skin.

7. How do I dispose of my Bydureon pen?

You will need a puncture-resistant container that is large enough to hold the entire pen with a 

used needle attached. Be sure the container has a lid. You may use a biohazard container, 

another hard plastic container, or a metal container. A container is not included in the carton.

Ask your pharmacist how to safely throw away the container with used pens and needles. Do 

not throw the container in your household waste.



138

INSTRUCTIONS FOR THE USER 
Read these instructions carefully before use
Read also the Package Leaflet in your carton

Bydureon 2 mg prolonged-release suspension for injection in pre-filled pen
exenatide

Once weekly
For subcutaneous use only
Single-dose pre-filled pen 
BCise is the name of the pre-filled pen device used to inject your Bydureon medicine.

Before You Begin

The Bydureon BCise pen:
− Is a single use, fixed dose pen that automatically injects your medicine.
− Comes in the locked position before you use it. Do not unlock the pen until you are ready to inject 

it.
− Needle is hidden. You do not see it before, during, or after using the pen.

• Do not use the pen if any parts look to be broken or damaged.
• Store flat in the refrigerator between 2 °C to 8 °C.
• Bydureon BCise pen should not be used by people who are blind or cannot see well, unless 

another person who is trained to use this device can help.
• Keep the pen, and all medicines, out of the reach of children.

Before Use 

Your doctor or diabetes nurse should teach you how to inject this medicine before you use it for the 
first time

Figure A

Supplies needed to give your injection:

Medicine

Window Locked PositionOrange Cap



139

• Bydureon BCise pen • Alcohol swab • A clean, flat surface • Puncture-resistant container (see 
“disposal” instructions at the end of these instructions)

STEP 1: Prepare for injection

A. Let your pen come to room temperature. 

Remove 1 pen from the refrigerator and rest it 

flat for 15 minutes. Bydureon BCise pen can 

be kept at room temperature for up to 4 weeks.

B. Check the expiration date (labelled EXP) 

printed on the pen label. Do not use the pen 

past the expiration date.

Figure B

Figure C

C. Wash your hands.

D. Choose your injection site.

In either your stomach, thigh, or back of the upper arm, see Figure D. 

Each week you can use the same area of your body, but choose a different injection site in that area of your 
body. 

Clean the area with an alcohol swab.

Figure D

Front Back

WAIT
Minutes



140

STEP 2: Mix the medicine

A. Look in the window.

You may see white medicine along the sides, 
bottom or top. This means the medicine is not 
mixed evenly. 

Figure E

B. Shake the pen hard, 

in an up-and-down motion, until the medicine is 
mixed evenly and you do not see any white 
medicine along the sides, bottom or top. Shake for 
at least 15 seconds.

Figure F

C. Check the mix. 

Hold the pen up to the light and look through both sides and the bottom of the window. If not mixed well, 

repeat Step 2 and check again.

Figure G

Look

Shake Hard

NOT Mixed Well

Uneven mix

White medicine on

bottom, top, or sides

Mixed Well

Even mix

Cloudy

It’s OK to see bubbles



141

Figure H

Do not go to the next step unless your medicine is mixed well. To get a full dose, the medicine must be 

mixed well and look cloudy.

If not mixed well, continue to shake hard.

STEP 3: Prepare the Pen

Important: After the medicine is fully mixed, you must complete the preparation steps right away, and 

inject to get the full dose. Do not save it to use later.

Only unlock the pen when you are ready to inject.

A. Unlock the pen.

Hold the pen up straight with the orange cap toward the ceiling. Turn the knob from the Lock to the 

Unlock position until you hear a click.

Figure I

Figure J

B. While still holding the pen straight up, firmly unscrew the orange cap.

Click

Lock

Unlock



142

• You may need to turn the cap a few times before it loosens (if you hear clicking you are turning in 
the wrong direction).

• Continue holding the pen upright to prevent the medicine from accidently leaking.
• A green shield will pop up after the cap is removed. The green shield hides the needle.
It is normal to see a few drops of liquid inside the cap. Do not recap the pen.

Throw away the cap.

           

    Figure K                                           Figure L

           

Figure M                                                                Figure N

STEP 4: Inject the Dose

A. Inject and hold:

• Push the pen against your skin. You will hear a “click” when the injection begins.
• Keep holding the pen against the skin for 15 seconds. This is to make sure you get the full 

dose.

Hold upright & firmly unscrew

Green shield pops upRemoved Cap

Hidden 
Needle



143

Figure O

B. Make sure you received your full dose.

After you receive your injection, you will see an orange rod in the window. After you lift the pen from 
your skin, the green shield will move back up to lock over the needle. See the Common Questions & 
Answers for what to do if you do not see the orange rod in the window after injection.

Figure P

C. Disposal.

Properly dispose of your pen right away after 
use, as instructed by your doctor, pharmacist or 
diabetes nurse. 
You will need a puncture-resistant container that:
 is large enough to hold the entire pen,

 has a lid,

 does not leak,

 is properly labelled to warn of hazardous 

waste inside the container. 

You may use a biohazard container, another hard 
plastic container, or a metal container.

  

    Figure Q

Seconds

PUSH & HOLD

Click

Orange
Rod



144

Common Questions and Answers

1. Where is the needle?

The needle is attached to the pen and covered by the orange cap.
When you unscrew the orange cap, the green shield keeps the needle covered until you inject.
For more information, please see Figure N in Step 3B in the Instructions for the User.

2. How do I know if the medicine is fully mixed?

After shaking the pen, look through both sides of the window. You should not see any white medicine 
along the bottom, top, or sides. If you see white medicine, it is unmixed. To mix, shake the pen hard 
until the white medicine is no longer on the bottom, top, or sides. The medicine should look even 
throughout (see pictures in Figure G and Figure H, Step 2C).

3. Why do I need to hold the pen upright while removing the orange cap?

Holding the pen with the orange cap straight up helps prevent the medicine from leaking. It is normal 
to see a few drops of medicine inside the orange cap after you unscrew it.

4. Why should I inject my medicine right away after mixing it?

If you do not inject your medicine right away after mixing, the medicine may separate, and you will 
not get your full dose. You can re-mix your medicine if your pen is in the locked position. However, 
after you unlock it, you must complete the preparation steps right away and inject to get the full dose. 
You cannot save it for later use.

5. How do I know I gave myself the full dose of medicine?

To be sure you get your full dose, press and hold the pen against your skin.
You will feel the needle go into your skin. Hold the needle against your skin for 15 seconds. This will 
allow enough time for all the medicine to go from the pen to under your skin. After removing the 
needle, look for the orange rod in the window as a way to tell that the dose has been given. If the 
orange rod does not appear, contact the local representative of the Marketing Authorisation Holder 
(see section 6 of the Package Leaflet for a list of contacts by country).

6. Why should I store my pen flat in the refrigerator?

Pens stored vertically (with the needle up or down) are more difficult to mix. The medicine can still be 
fully mixed but it will take more shaking and more time.

7. How do I dispose of my Bydureon BCise pen?

Do not throw away the pen in your household waste. You will need a puncture-resistant container that 
is large enough to hold the entire pen. Be sure the container has a lid. You may use a biohazard 
container, another hard plastic container, or a metal container. A container is not included in the 
carton.
Do not recycle the container with used pens. Ask your pharmacist how to safely throw it away. Do not 
throw the container in your household waste.

8. What if the device malfunctions and I cannot unlock it?

Review the Instructions for the User Step 3 to confirm the order of operations, then contact the local 
representative of the Marketing Authorisation Holder (see section 6 of the Package Leaflet for a list of 
contacts by country). Do not try to unlock with excessive force or tools.

9. What if the device malfunctions and I cannot remove the orange cap?



145

Review the Instructions for the User Step 3 to confirm the order of operations, also confirm that the 
knob is fully in the unlocked position, then contact the local representative of the Marketing 
Authorisation Holder (see section 6 of the Package Leaflet for a list of contacts by country). Do not 
use tools or try to force the cap off.

10. Where to learn more about Bydureon BCise pen

 Talk with your doctor, pharmacist or diabetes nurse
 Read the Package Leaflet carefully.

How to Store Bydureon BCise pen 
• Store flat in the refrigerator between 2 °C to 8 °C.
• Each pen can be kept at room temperature not to exceed 30 °C for no more than a total of 4 weeks, 

if needed.
• Store in packaging provided to protect from light until you are ready to prepare and use your dose.
• Do not use past the expiration date. The expiration date is labelled EXP.
• Keep the pen clean and away from spills.


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURERS RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET