BYDUREON 2mg suspension injection with prolonged release in pen medication leaflet

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

Each pre-filled pen contains 2 mg of exenatide. After suspension, each pen delivers a dose of 2 mg in0.65 mL.

For the full list of excipients, see section 6.1.

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.

Bydureon is indicated in adults, adolescents and children aged 10 years and above with type 2 diabetesmellitus to improve glycaemic control in combination with other glucose-lowering medicinal productsincluding basal insulin, when the therapy in use, together with diet and exercise, does not provideadequate 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.

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, whichgenerally improve within the first two weeks after initiation of therapy. Patients switching between theprolonged-release exenatide products (Bydureon or Bydureon BCise) may do so, with no expectedrelevant 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 tosulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce therisk of hypoglycaemia (see section 4.4). Combination therapy with thiazolidinedione was only studiedin adult patients.

Prolonged-release exenatide should be administered once a week on the same day each week. The dayof weekly administration can be changed if necessary as long as the last dose was administered at leastthree days before. Prolonged-release exenatide can be administered at any time of day, with or withoutmeals.

If a dose is missed, it should be administered as soon as practical, provided the next regularlyscheduled dose is due in 3 days or more. Thereafter, patients can resume their usual once weeklydosing schedule.

If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, the patient should notadminister the missed dose, but instead resume prolonged-release exenatide on the next regularlyscheduled dosing day.

The use of prolonged-release exenatide does not require additional self-monitoring. Blood glucoseself-monitoring is necessary to adjust the dose of sulphonylurea and of insulin, particularly whenprolonged-release exenatide therapy is started and insulin is reduced. A stepwise approach to insulindose reduction is recommended.

If a different glucose-lowering treatment is started after the discontinuation of prolonged-releaseexenatide, consideration should be given to the prolonged release of the product (see section 5.2).

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).

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 orsevere renal impairment (glomerular filtration rate [GFR] < 30mL/min) (see section 4.4).

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

No dose adjustment is required for adolescents and children aged 10 years and above. No data areavailable for children below 10 years of age (see sections 5.1 and 5.2).

Subcutaneous use

Prolonged-release exenatide is for self-administration by the patient. Each pen can only be used by oneperson and is for single use.

Prior to initiation of prolonged-release exenatide, it is strongly recommended that patients andcaregivers be trained by their healthcare professional. The “Instructions for the User”, provided in thecarton, must be followed carefully.

Each dose should be administered in the abdomen, thigh, or the back of the upper arm as asubcutaneous injection immediately after suspension of the powder in the solvent.

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

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

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

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

Prolonged-release exenatide is not a substitute for insulin. Diabetic ketoacidosis has been reported ininsulin-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.

In patients with end-stage renal disease receiving dialysis, single doses of immediate-release exenatideincreased frequency and severity of gastrointestinal adverse reactions; therefore, prolonged-releaseexenatide is not recommended for use in patients with end-stage renal disease or severe renalimpairment (GFR < 30mL/min).

There have been uncommon events of altered renal function with exenatide, including increased serumcreatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimesrequiring haemodialysis. Some of these events occurred in patients experiencing events that may affecthydration, including nausea, vomiting, and/or diarrhoea and/or receiving medicinal products known toaffect renal function/hydration status. Concomitant medicinal products included angiotensinconverting enzymes inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinalproducts and diuretics. Reversibility of altered renal function has been observed with supportivetreatment 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 notrecommended in patients with severe gastrointestinal disease.

Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. Inclinical studies of prolonged-release exenatide, acute pancreatitis occurred in 0.3% of patients. Therehave been spontaneously reported events of acute pancreatitis with prolonged-release exenatide.

Resolution of pancreatitis has been observed with supportive treatment, but very rare cases ofnecrotising or haemorrhagic pancreatitis and/or death have been reported. Patients should be informedof the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis issuspected, 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 ahistory of pancreatitis.

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 hasnot been studied. The concurrent use of prolonged-release and immediate-release exenatide has notbeen studied and is not recommended.

Lack of efficacy due to anti-drug antibodies (ADA) in paediatric patients

Paediatric patients are possibly more prone to developing high titers of ADA than adults (see section4.8). Patients with higher titre antibodies may have an attenuated HbA1c response.

No commercial testing of anti-drug antibodies is available, but if targeted glycaemic control is notachieved despite confirmed patient compliance, regardless of the reason for the lack of efficacy,physicians should consider alternative antidiabetic therapy.

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).

The risk of hypoglycaemia was increased when prolonged-release exenatide was used in combinationwith a sulphonylurea in clinical studies. Furthermore, in the clinical studies, patients on asulphonylurea combination, with mild renal impairment had an increased incidence of hypoglycaemiacompared to patients with normal renal function. To reduce the risk of hypoglycaemia associated withthe 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 bemonitored for signs and symptoms of cholelithiasis.

After discontinuation, the effect of prolonged-release exenatide may continue as plasma levels ofexenatide decline over 10 weeks. Choice of other medicinal products and dose selection should beconsidered accordingly, as adverse reactions may continue and efficacy may, at least partly, persistuntil exenatide levels decline.

Aspiration in association with general anaesthesia or deep sedation

Cases of pulmonary aspiration have been reported in patients receiving GLP-1 receptor agonistsundergoing general anaesthesia or deep sedation. Therefore, the increased risk of residual gastriccontent due to delayed gastric emptying (see section 4.8) should be considered prior to performingprocedures with general anaesthesia or deep sedation.

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

Sulphonylureas

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

The results of a study using paracetamol as a marker of gastric emptying suggest that the effect ofprolonged-release exenatide to slow gastric emptying is minor and not expected to cause clinicallysignificant reductions in the rate and extent of absorption of concomitantly administered oralmedicinal products. Therefore, no dose adjustments for medicinal products sensitive to delayed gastricemptying are required.

When 1,000 mg paracetamol tablets were administered, either with or without a meal, following14 weeks of prolonged-release exenatide therapy, no significant changes in paracetamol AUC wereobserved 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) and1.3 hours (fed).

The following interaction studies have been conducted using 10 mcg immediate-release exenatide butnot prolonged-release exenatide:

A delay in tmax of about 2 h was observed when warfarin was administered 35 min afterimmediate-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-releaseexenatide. INR should be monitored during initiation of prolonged-release exenatide therapy inpatients 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 wasdelayed about 4 h when immediate-release exenatide was administered concomitantly with a singledose of lovastatin (40 mg) compared with lovastatin administered alone. In 30-weekplacebo-controlled clinical studies with immediate-release exenatide, concomitant use of exenatideand HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles (seesection 5.1). No predetermined dose adjustment is required; however, lipid profiles should bemonitored as appropriate.

Digoxin and lisinopril

In interaction studies of the effect of immediate-release exenatide on digoxin and lisinopril there wereno 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 mcglevonorgestrel) one hour before immediate-release exenatide did not alter the AUC, Cmax or Cmin ofeither ethinyl estradiol or levonorgestrel. Administration of the oral contraceptive 35 minutes afterexenatide 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. Thereduction in Cmax is of limited clinical relevance and no adjustment of dosing of oral contraceptives isrequired.

Interaction studies with exenatide have only been performed in adults.

Due to the long washout period of prolonged-release exenatide, women of childbearing potentialshould use contraception during treatment with prolonged-release exenatide. This medicinal productshould be discontinued at least 3 months before a planned pregnancy.

There are no adequate data from the use of prolonged-release exenatide in pregnant women. Studies inanimals 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 isrecommended.

It is unknown whether exenatide is excreted in human milk. Prolonged-release exenatide should not beused during breast-feeding.

No fertility studies in humans have been conducted.

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

The most frequent adverse reactions in adults were mainly gastrointestinal related (nausea which wasthe most frequent reaction and associated with the initiation of treatment and decreased over time, anddiarrhoea). In addition, injection site reactions (pruritus, nodules, erythema), hypoglycaemia (with asulphonylurea), and headache occurred. Most adverse reactions associated with prolonged-releaseexenatide were mild to moderate in intensity.

The frequency of adverse reactions of prolonged-release exenatide identified from clinical studies andspontaneous reports in adults (not observed in clinical studies, frequency not known) are summarisedin Table 1 below.

In the prolonged-release exenatide clinical studies in adults, background therapies included diet andexercise, metformin, a sulphonylurea, a thiazolidinedione, a combination of oral glucose-loweringmedicinal products or a basal insulin.

The reactions are listed below as MedDRA preferred term by system organ class and absolutefrequency. 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 notknown (cannot be estimated from the available data).

Table 1: Adverse reactions of prolonged-release exenatide identified from clinical studies andspontaneous reports in adults

System organ class Frequency of occurrence/adverse reactionterms

Very Common Uncommon Rare Very rare Notcommon known

Drug-induced X4thrombocytopenia

Cholecystitis X6

Cholelithiasis X6

Anaphylactic reaction X1

Hypoglycaemia (with X1a sulphonylurea)

Hypoglycaemia (with X2,3insulin)

Decreased appetite X1

Dehydration X1

Headache X1

Dizziness X1

Dysgeusia X1

Somnolence X1

Intestinal obstruction X1

Acute pancreatitis (see X1section 4.4)

System organ class Frequency of occurrence/adverse reactionterms

Very Common Uncommon Rare Very rare Notcommon known

Nausea X1

Vomiting X1

Diarrhoea X1

Dyspepsia X1

Abdominal pain X1

Gastroesophageal X1reflux disease

Abdominal distension X1

Eructation X1

Constipation X1

Flatulence X1

Delayed gastric X5emptying

Macular and papular X4rash

Pruritus, and/or X1urticaria

Angioneurotic oedema X4

Injection site abscesses X4and cellulitis

Hyperhidrosis X1

Alopecia X1

Altered renal function, X1including acute renalfailure, worsenedchronic renal failure,renal impairment,increased serumcreatinine (see section4.4).

Injection site pruritus X1

Fatigue X1

Injection site erythema X1

Injection site rash X1

Asthenia X1

Feeling jittery X1

International X4normalised ratioincreased (see section4.4)1 Rate based on twelve prolonged-release exenatide completed long-term efficacy and safety studiesn = 2868 total (patients on sulphonylurea n=1002).

2 Based on hypoglycaemic events that 1. Result in loss of consciousness, seizure, or coma whichresolves after administration of glucagon or glucose OR 2. Require third-party assistance to resolvebecause 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 exenatideas add-on to insulin glargine study (N=231).4 Rate based on prolonged-release exenatide spontaneous reports data (unknown denominator).5 Rate based on sixteen prolonged-release exenatide completed long term efficacy and safety studiesn = 4086 total.6 Rate based on BYDUREON completed safety and efficacy studies (n=3560 total); includes

DURATION 7 and DURATION 8 studies.

Drug-induced thrombocytopenia

Drug-induced thrombocytopenia (DITP) with exenatide-dependent anti-platelet antibodies has beenreported in adults in the postmarketing setting. DITP is an immune-mediated reaction that is caused bydrug-dependent platelet-reactive antibodies. These antibodies cause destruction of platelets in thepresence of the sensitizing drug.

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

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

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

When prolonged-release exenatide was added to basal insulin, no initial dose adjustment of insulinwas required. Prolonged-release exenatide in combination with basal insulin showed no clinicallysignificant differences in the incidence of hypoglycaemic episodes compared to insulin. There were noepisodes of major hypoglycaemia in the prolonged-release exenatide with insulin group.

Nausea

The most frequently reported adverse reaction in adults was nausea. In patients treated withprolonged-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. Withcontinued 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% forprolonged-release exenatide treated patients, 5% for immediate-release exenatide treated patients. Themost common adverse events leading to withdrawal in either treatment group were nausea andvomiting. Withdrawal due to nausea or vomiting each occurred in < 1% for prolonged-releaseexenatide treated patients and 1% for immediate-release exenatide treated patients.

Injection site reactions in adults were observed more frequently in prolonged-release exenatide treatedpatients versus comparator-treated patients (16% versus range of 2-7%) during the 6-month controlledphase of studies. These injection site reactions were generally mild and usually did not lead towithdrawal 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, consistentwith the known properties of poly (D,L-lactide co-glycolide) polymer microsphere formulations. Mostindividual nodules were asymptomatic, did not interfere with study participation and resolved over 4to 8 weeks.

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals,patients may develop antibodies to exenatide following treatment with prolonged-release exenatide. Inmost 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 individualpatient.

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

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

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

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

Rapid weight loss

In a 30-week study in adults, approximately 3% (n = 4/148) of prolonged-release exenatide treatedpatients experienced at least one time period of rapid weight loss (recorded body weight loss betweentwo consecutive study visits of greater than 1.5 kg/week).

A mean increase in heart rate (HR) of 2.6 beats per minute (bpm) from baseline (74 bpm) wasobserved in pooled prolonged-release exenatide clinical studies in adults. Fifteen percent ofprolonged-release exenatide treated patients had mean increases in HR of ≥ 10 bpm; approximately5% to 10% of subjects within the other treatment groups had mean increases in HR of ≥ 10 bpm.

The exenatide safety profile in a clinical study with adolescents and children aged 10 years or older(see section 5.1) was similar to that observed in the studies in adults.

In the paediatric study there were no major hypoglycaemia events.

During the 24-week double-blind treatment period, one patient (1.7%) in the prolonged-releaseexenatide group and one patient (4.3%) in the placebo group had minor hypoglycaemia (defined as anon-major hypoglycaemia event that had symptoms consistent with hypoglycaemia and a glucosevalue less than 3 mmol/L [54 mg/dL] prior to treating the episode). Both patients were receivinginsulin as background therapy.

Other hypoglycaemia events, episodes that did not meet either major or minor criteria, were reportedby the investigator in 8 patients (13.6%) and 1 patient (4.3%) in the prolonged-release exenatide andplacebo groups, respectively. Out of these, 6 patients in the prolonged-release exenatide group and1 patient in the placebo group received insulin as background therapy.

In the paediatric study the maximum antibody titre obtained at any time during the study was low(<625) for approximately 29.3% of patients and high (≥625) for approximately 63.8% of patients. Thepercentage of patients with positive antibody titres peaked at approximately Week 12. As the studycontinued to Week 52 the percentage of patients with high titres had decreased (30.4%) andpercentage of the patients with low titres (41.3%) had increased. Patients with higher titre antibodiesmay have an attenuated HbA1c response (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

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

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

Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that exhibits severalantihyperglycaemic actions of glucagon-like peptide-1 (GLP-1). The amino acid sequence ofexenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind to and activatethe known human GLP-1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/orother 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 incombination with metformin and/or a thiazolidinedione, no increase in the incidence ofhypoglycaemia was observed over that of placebo in combination with metformin and/or athiazolidinedione which may be due to this glucose-dependent insulinotropic mechanism (see section4.4).

Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in patientswith 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 tohypoglycaemia.

Exenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears inthe circulation.

Administration of exenatide has been shown to reduce food intake, due to decreased appetite andincreased satiety.

Exenatide improves glycaemic control through the sustained effects of lowering both postprandial andfasting 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 onceweekly administration.

A pharmacodynamic study with exenatide demonstrated in patients with type 2 diabetes (n = 13) arestoration of first phase insulin secretion and improved second phase insulin secretion in response toan intravenous bolus of glucose.

The results of long-term clinical studies of prolonged-release exenatide are presented below; thesestudies comprised 1356 adult 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) enrolled14,752 adult subjects with type 2 diabetes and any level of CV risk when added to the current usualcare.

In two studies in adults prolonged-release exenatide 2 mg once weekly has been compared toimmediate-release exenatide 5 mcg given twice daily for 4 weeks followed by immediate-releaseexenatide 10 mcg given twice daily. One study was of 24 weeks in duration (n = 252) and the other of30 weeks (n = 295) followed by an open-labelled extension where all patients were treated withprolonged-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 HbA1cmeasurement (Weeks 4 or 6).

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

A clinically relevant effect of prolonged-release exenatide and immediate-release exenatide treatedsubjects was observed on HbA1c, regardless of the background anti-diabetic therapy in both studies.

Clinically and statistically significantly more subjects on prolonged-release compared toimmediate-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 weightcompared 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 toprolonged-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 patientsincluded in the extension phase), HbA1c gradually increased over time from Week 52 onwards, butwas still reduced compared to baseline after 7 years (-1.5%). Weight loss was sustained over 7 years inthese patients.

Table 2: Results of two studies of prolonged-release versus immediate-release exenatide incombination with diet and exercise alone, metformin and/or sulphonylurea and metforminand/or thiazolidinedione (intent-to-treat patients)24-Week Study Prolonged- Immediate-release releaseexenatide 2 mg exenatide10 mcg twicedaily

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 -0.67 (-0.94, -0.39)**treatments (95% CI)

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 -0.95 (-1.91, 0.01)treatments (95% CI)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 -0.33 (-0.54, -0.12)*treatments (95 % CI)

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 -0.08 (-1.29, 1.12)treatments (95% CI)

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

A study of 26-week duration has been conducted in adults, in which prolonged-release exenatide 2 mgis compared to insulin glargine once daily. Compared with insulin glargine treatment, prolonged-release exenatide demonstrated a superior change in HbA1c, significantly lowered mean body weightand was associated with fewer hypoglycaemic events (Table 3).

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

Prolonged- Insulinrelease exenatide glargine12 mg

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 -0.16 (-0.29, -0.03)*treatments (95% CI)

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 -4.05 (-4.57, -3.52)*treatments (95% CI)

SE = standard error, CI = confidence interval, * p < 0.051 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/dayfor 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 andweight control, compared to the insulin glargine treatment. Safety findings at 156 weeks wereconsistent with those reported at 26 weeks.

In a 26-week double-blind study prolonged-release exenatide was compared to maximum daily dosesof sitagliptin and pioglitazone in adult subjects also using metformin. All treatment groups had asignificant reduction in HbA1c compared to baseline. Prolonged-release exenatide demonstratedsuperiority to both sitagliptin and pioglitazone with respect to change in HbA1c from baseline.

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

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

Prolonged- Sitagliptin Pioglitazonerelease 100 mg 45 mgexenatide2 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 -0.63 (-0.89, -0.37)**between treatments (95% CI) versussitagliptin

Mean difference change from baseline -0.32 (-0.57, -0.06)*between treatments (95% CI) versuspioglitazone

Patients (%) achieving HbA1c ≤ 7% 62 36 49

Change in fasting serum glucose -1.8 (± 0.2) -0.9 (± 0.2) -1.5 (± 0.2)(mmol/L) (± SE)

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 -1.54 (-2.35, -0.72)*between treatments (95% CI) versussitagliptin

Mean difference change from baseline -5.10 (-5.91, -4.28)**between treatments (95% CI) versuspioglitazone

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

In a 28-week, double-blind study in adults, the combination of prolonged-release exenatide anddapagliflozin was compared to prolonged-release exenatide alone and dapagliflozin alone in subjectsalso using metformin. All treatment groups had a reduction in HbA1c compared to baseline. Theprolonged-release exenatide and dapagliflozin treatment group showed superior reductions in HbA1cfrom baseline compared to prolonged-release exenatide alone and dapagliflozin alone (Table 5).

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

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

Prolonged-release Prolonged-release Dapagliflozinexenatide 2 mg QW exenatide 2 mg 10 mg QD+ QW +

Dapagliflozin 10 mg + Placebo QW

QD Placebo QD

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 changefrom baseline between -0.38* -0.59**combination and singleactive medicinal product (-0.63, -0.13) (-0.84, -0.34)(95% CI)

Patients (%) achieving

HbA 45 27 191c < 7%

Mean change from baselinein fasting plasma glucose -3.7 (±0.2) -2.5 (±0.2) -2.7 (±0.2)(mmol/L) (±SE)a

Mean difference in changefrom baseline betweencombination and single -1.12** -0.92**active medicinal product (-1.55, -0.68) (-1.36, -0.49)(95%CI)

Mean change from baselinein 2-hour postprandialplasma glucose (mmol/L) -4.9 (±0.2) -3.3 (±0.2) -3.4 (±0.2)(±SE)a

Mean difference in changefrom baseline betweencombination and single -1.54** -1.49**active medicinal product (-2.10, -0.98) (-2.04, -0.93)(95% CI)

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 changefrom baseline betweencombination and single -2.00** -1.33**active medicinal product (-2.79, -1.20) (-2.12, -0.55)(95% CI)

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

In a 28-week double-blind study in adults, prolonged-release exenatide added to insulin glargine aloneor with metformin was compared to placebo added to insulin glargine alone or with metformin. Insulinglargine 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 incombination with insulin glargine alone or with metformin (intent-to-treat patients)

Prolonged-release Placeboexenatide 2 mg + Insulin glarginea+ 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 -0.74*between treatments (95% CI) (-0.94, -0.54)

Patients (%) achieving HbA ≤ 7%c1c 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 -1.52*between treatments (95% CI) (-2.19, -0.85)

Change from baseline in 2-hour postprandial -1.6 (±0.3) -0.1 (±0.3)plasma glucose (mmol/L) (± SE)b,d

Mean difference in change from baseline -1.54*between treatments (95% CI) (-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 exenatidegroup 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 28are 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, andtreatment by week interaction as fixed factors, and baseline value as a covariate. The absolute changein 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 studymedication.

EXSCEL was a pragmatic cardiovascular (CV) outcome study in adult patients with type 2 diabetesand any level of CV risk. A total of 14,752 patients were randomised 1:1 to either prolonged-releaseexenatide 2 mg once weekly or placebo, added to the current usual care which could include SGLT2inhibitors. Patients were followed as in routine clinical practice for a median of 38.7 months with amedian treatment duration of 27.8 months. The vital status was known at the end of the study for98.9% 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 was13.1 years. The mean HbA1c was 8.1%. Approximately 49.3% had mild renal impairment (estimatedglomerular filtration rate [eGFR] ≥ 60 to ≤ 89 mL/min/1.73 m2) and 21.6% had moderate renalimpairment (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 tofirst confirmed Major Adverse Cardiac Event (MACE): cardiovascular (CV)-related death, nonfatalmyocardial infarction (MI) or nonfatal stroke. All-cause mortality was the initial secondary endpointassessed.

Prolonged-release exenatide did not increase the cardiovascular risk in patients with type 2 diabetesmellitus 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 HRfor MACE was 0.86 (95% CI: 0.77-0.97) in patients with baseline eGFR ≥ 60 mL/min/1.73 m2 and1.01 (95% CI: 0.86-1.19) in patients with baseline eGFR < 60 mL/min/1.73 m2. The results of theprimary composite and secondary cardiovascular endpoints are shown in Figure 2.

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

Exenatide

Placebo

Exenatide vs Placebo:

HR (95% CI) 0.91 (0.832,1 004)

Months from Randomization

Number at Risk

Exenatide

Placebo

HR=hazard ratio, CI=confidence interval

Patients with an Event (%)

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

Hazard Ratio Exenatide Placebon (%) Event Rate n (%) Event Rate HR (95% CI)1

MACE )

All-cause death

CV-related death

Myocardial Infarction

Stroke

Hospitalisation for ACS

Hospitalisation for HF<-Exenatide favored- -Placebo favored->

ACS=acute coronary syndrome; CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazardratio; 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 CVevent, 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 placebogroup (exposure-adjusted incidence of 15.7 per 100 pt-year). A reduction in HbA1c was observed overthe course of the trial with an overall treatment difference of -0.53% (prolonged-release exenatide vs.placebo).

A reduction in body weight compared to baseline has been observed in all prolonged-release exenatidestudies. In the 4 comparator-controlled studies, this reduction in body weight was seen in patientstreated with prolonged-release exenatide irrespective of the occurrence of nausea although thereduction was larger in the group with nausea (mean reduction of -2.9 kg to -5.2 kg with nauseaversus -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 weightand HbA1c ranged from 70 to 79% (the proportion of patients who had a reduction of HbA1c rangedfrom 88 to 96%).

Plasma/serum glucose

Treatment with prolonged-release exenatide resulted in significant reductions in fasting plasma/serumglucose concentrations, these reductions were observed as early as 4 weeks. In the placebo-controlledstudy with insulin glargine, the change from baseline to Week 28 in fasting plasma glucosewas -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 fastingplasma glucose concentrations was durable through 52 weeks.

Beta-cell function

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

A reduction in systolic blood pressure was observed in the 4 comparator-controlled prolonged-releaseexenatide studies (2.9 mmHg to 4.7 mmHg). In the 30-week immediate-release exenatide comparatorstudy both prolonged-release and immediate-release exenatide significantly reduced systolic bloodpressure from baseline (4.7±1.1 mmHg and 3.4±1.1 mmHg, respectively); the difference between thetreatments 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 systolicblood pressure was -2.6 mmHg for the prolonged-release exenatide group and -0.7 mmHg for theplacebo group.

Treatment with prolonged-release exenatide and dapagliflozin combination at Week 28 resulted in asignificant mean change reduction of -4.3±0.8 mmHg in systolic blood pressure compared toprolonged-release exenatide alone of -1.2±0.8 mmHg (p < 0.01) or to dapagliflozin alone of -1.8±0.8mmHg (p < 0.05).

Fasting lipids

Prolonged-release exenatide has shown no negative effects on lipid parameters.

The efficacy and safety of prolonged-release exenatide 2 mg once weekly or placebo was evaluated ina randomized, double-blind, placebo-controlled, parallel-group study in adolescents and children aged10 years and above with type 2 diabetes treated with diet and exercise alone or in combination with astable dose of oral antidiabetic agents and/or insulin. The prolonged-release exenatide was superior toplacebo in reducing HbA1c after 24 weeks (Table 7).

Table 7: Results of one 24-week study of prolonged-release exenatide versus placebo inadolescent and paediatric patients aged 10 years and above (intent-to-treat patients)

Prolonged-release Placeboexenatide 2 mg QW

QW

Intent-to-Treat Population (N) 58 24

Mean HbA1c (%)

Baseline 8.11 8.22

Change from baseline (± SE) -0.36 (0.18) 0.49 (0.27)

Mean difference change from baselinevs. Placebo (95% CI)a -0.85 (-1.51, -0.19)*

Mean fasting plasma glucose (mmol/L)

Baseline 9.24 9.08

Change from baseline (± SE) -0.29 (0.424) 0.91 (0.63)

Mean difference change from baselinevs. Placebo (95% CI)b -1.2 (-2.72, 0.32)

Mean body weight (kg)

Baseline 100.33 96.96

Change from baseline (± SE) -0.59 (0.67) 0.63 (0.98)

Mean difference change from baselinevs. Placebo (95% CI)b -1.22 (-3.59, 1.15)

Proportion achieving HbA1c <7.0% 31.0% 8.3%

Proportion achieving HbA1c ≤6.5% 19.0% 4.2%

Proportion achieving HbA1c <6.5% 19.0% 4.2%

*p=0.012a Adjusted LS mean and treatment group difference in the change from baseline values at each visit aremodeled using a MMRM including treatment group, region, visit, treatment group by visit interaction,baseline HbA1c and baseline HbA1c by visit interaction as fixed effects, using an unstructuredcovariance matrix.b Adjusted LS mean and treatment group difference in the change from baseline values at each visit aremodeled using a MMRM including treatment group, region, visit, treatment group by visit interaction,baseline value, screening HbA1c (< 9.0% or ≥ 9.0%), and baseline value by visit interaction as fixedeffects, using an unstructured covariance matrix.

The absorption properties of exenatide reflect the extended release properties of the prolonged-releaseexenatide formulation. Once absorbed into the circulation, exenatide is distributed and eliminatedaccording to its known systemic pharmacokinetic properties (as described in this section).

Following weekly administration of 2 mg prolonged-release exenatide, mean exenatide concentrationsexceeded minimal efficacious concentrations (~ 50 pg/mL) in 2 weeks with gradual increase in theaverage plasma exenatide concentration over 6 to 7 weeks. Subsequently, exenatide concentrations ofapproximately 151-265 pg/mL were maintained indicating that steady state was achieved. Steady-stateexenatide concentrations are maintained during the one-week interval between doses with minimalpeak to trough fluctuation from this average therapeutic concentration.

The mean apparent volume of distribution of exenatide following subcutaneous administration of asingle dose of exenatide is 28 L.

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtrationwith subsequent proteolytic degradation. The mean apparent clearance of exenatide is 9 L/h. Thesepharmacokinetic characteristics of exenatide are independent of the dose. Approximately 10 weeksafter discontinuation of prolonged-release exenatide therapy, mean plasma exenatide concentrationsfell below minimal detectable concentrations.

Population pharmacokinetic analysis of renal impaired patients receiving 2 mg prolonged-releaseexenatide 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.

No pharmacokinetic study has been performed in patients with hepatic insufficiency. Exenatide iscleared primarily by the kidney, therefore hepatic dysfunction is not expected to affect bloodconcentrations of exenatide.

Gender, race and body weight

Gender, race and body weight have no clinically relevant influence on exenatide pharmacokinetics.

Data in elderly are limited, but suggest no marked changes in exenatide exposure with increased ageup 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 15elderly subjects aged 75 to 85 years compared to 15 subjects aged 45 to 65 years likely related toreduced renal function in the older age group (see section 4.2).

The population pharmacokinetic analysis in adolescents and children with low ADA titre aged 10years and above with type 2 diabetes mellitus demonstrated that administration of exenatide extended-release (2 mg) resulted in exposure similar to that observed in adults.

Non-clinical data reveal no special hazards for humans based on conventional studies of safetypharmacology, repeat-dose toxicity, or genotoxicity conducted with immediate-release orprolonged-release exenatide.

Thyroid tumours have been observed in rats and mice with long acting GLP-1 receptor agonists. In a2-year rat carcinogenicity study with prolonged-release exenatide, an increased incidence of C-celladenomas and C-cell carcinomas was observed at doses ≥ 2-fold the human systemic exposure basedon 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 ofexenatide caused skeletal effects and reduced foetal and neonatal growth.

Powderpoly (D,L-lactide-co-glycolide)sucrose

Solventcarmellose sodiumsodium chloridepolysorbate 20sodium dihydrogen phosphate monohydratedisodium phosphate heptahydratewater for injectionssodium hydroxide (for pH adjustment)

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

3 years

After suspension

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

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 pensmust be used or discarded.

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

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

Each dual-chamber pen contains exenatide powder and solvent in a Type 1 glass cartridge sealed atone end with a chlorobutyl rubber stopper and an aluminium seal, and at the other end with achlorobutyl 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 thesupplied needles with the pen.

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

Not all pack sizes may be marketed.

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 powderin one chamber must be mixed with the solvent in the other chamber of the pre-filled pen. The solventshould be visually inspected prior to use. The solvent should only be used if it is clear and free ofparticulate matter. After suspension, the mixture should only be used if it is white to off white andcloudy. Please see the package leaflet and “Instructions for the User” for additional information onsuspension and administration.

Use only the supplied custom needles with the pen.

Prolonged-release exenatide must be injected subcutaneously immediately after mixing of the powderand 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 eachinjection.

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

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/11/696/003-004

Date of first authorisation: 17 June 2011

Date of latest renewal: 18 February 2016

Detailed information on this medicinal product is available on the website of the European Medicines

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