BYDUREON^® 2 mg powder and solvent for prolonged-release suspension for injection.

Each vial contains 2 mg of exenatide.

For a 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 for treatment of type 2 diabetes mellitus in combination with

• Metformin

• Sulphonylurea

• Thiazolidinedione

• Metformin and sulphonylurea

• Metformin and thiazolidinedione

in adults who have not achieved adequate glycaemic control on maximally tolerated doses of these oral therapies.

Posology

The recommended dose is 2 mg exenatide once weekly.

Patients switching from exenatide twice daily (BYETTA) to BYDUREON may experience transient elevations in blood glucose concentrations, which generally improve within the first two weeks after initiation of therapy.

When BYDUREON is added to existing metformin and/or thiazolidinedione therapy, the current dose of metformin and/or thiazolidinedione can be continued. When BYDUREON is added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce the risk of hypoglycaemia (see section 4.4).

BYDUREON 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 next dose is administered at least one day (24 hours) later. BYDUREON 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. Thereafter, patients can resume their once weekly dosing schedule. Two injections should not be given on the same day.

The use of BYDUREON does not require additional self-monitoring. Blood glucose self-monitoring may be necessary to adjust the dose of sulphonylurea.

If a different antidiabetic treatment is started after the discontinuation of BYDUREON, consideration should be given to the prolonged release of BYDUREON (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 patients with renal impairment). The clinical experience in patients > 75 years is very limited (see section 5.2).

Patients with renal impairment

No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50 to 80 ml/min). Clinical experience in patients with moderate renal impairment (creatinine clearance 30 to 50 ml/min) is very limited (see section 5.2). BYDUREON is not recommended in these patients.

BYDUREON is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 ml/min) (see section 4.4).

Patients with hepatic impairment

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

Paediatric population

The safety and efficacy of BYDUREON in children and adolescents aged under 18 years have not yet been established (see section 5.2). No data are available.

Method of administration

BYDUREON is for self administration by the patient. Each kit should be used by one person only and is for single use.

Appropriate training is recommended for non-healthcare professionals administering the product. The “Instructions for the User”, provided in the carton, must be followed carefully by the patient.

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.

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

Hypersensitivity to the active substance or to any of the excipients.

BYDUREON should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

BYDUREON must not be administered by intravenous or intramuscular injection.

This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially “sodium-free”.

Renal impairment

In patients with end-stage renal disease receiving dialysis, single doses of exenatide twice daily increased frequency and severity of gastrointestinal adverse reactions, therefore BYDUREON is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 ml/min). The clinical experience in patients with moderate renal impairment is very limited and the use of BYDUREON is not recommended.

There have been rare, spontaneously reported 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 agents, including exenatide.

Severe gastrointestinal disease

BYDUREON 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 BYDUREON is not recommended in patients with severe gastrointestinal disease.

Acute pancreatitis

There have been rare, spontaneously reported events of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotizing or haemorrhagic pancreatitis and/or death have been reported. If pancreatitis is suspected, BYDUREON and other potentially suspect medicinal products should be discontinued. Treatment with BYDUREON should not be resumed after pancreatitis has been diagnosed.

Concomitant medicinal products

The concurrent use of BYDUREON with insulin, 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 BYDUREON and exenatide twice daily (BYETTA) has not been studied and is not recommended.

Hypoglycaemia

The risk of hypoglycaemia was increased when BYDUREON was used in combination with a sulphonylurea in clinical trials. 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.

Interaction with warfarin

There have been some reported cases of increased INR (International Normalized Ratio), sometimes associated with bleeding, with concomitant use of warfarin and exenatide (see section 4.5).

Discontinuation of treatment

After discontinuation, the effect of BYDUREON 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.

The results of a study using paracetamol as a marker of gastric emptying suggest that the effect of BYDUREON 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 BYDUREON therapy, no significant changes in paracetamol AUC were observed compared to the control period. Paracetamol C_max decreased by 16 % (fasting) and 5 % (fed) and t_max was increased from approximately 1 hour in the control period to 1.4 hours (fasting) and 1.3 hours (fed).

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).

The following interaction studies have been conducted using 10 μg exenatide twice daily but not exenatide once weekly:

Interaction studies with exenatide have only been performed in adults.

Hydroxy Methyl Glutaryl Coenzyme A reductase inhibitors

Lovastatin AUC and C_max were decreased approximately 40 % and 28 %, respectively, and t_max was delayed about 4 h when exenatide twice daily was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In exenatide twice daily 30-week placebo-controlled clinical trials, 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.

Warfarin

A delay in t_max of about 2 h was observed when warfarin was administered 35 min after exenatide twice daily. No clinically relevant effects on C_max or AUC were observed. Increased INR has been reported during concomitant use of warfarin and exenatide twice daily. INR should be monitored during initiation of BYDUREON therapy in patients on warfarin and/or cumarol derivatives (see section 4.8).

Digoxin and lisinopril

In interaction studies of the effect of exenatide twice daily on digoxin and lisinopril there were no clinical relevant effects on C_max or AUC, however, a delay in t_max of about 2 h was observed.

Ethinyl estradiol and levonorgestrel

Administration of a combination oral contraceptive (30 µg ethinyl estradiol plus 150 µg levonorgestrel) one hour before exenatide twice daily did not alter the AUC, C_max or C_min of either ethinyl estradiol or levonorgestrel. Administration of the oral contraceptive 35 minutes after exenatide did not affect AUC but resulted in a reduction of the C_max of ethinyl estradiol by 45 %, and C_max of levonorgestrel by 27-41 %, and a delay in t_max by 2-4 h due to delayed gastric emptying. The reduction in C_max is of limited clinical relevance and no adjustment of dosing of oral contraceptives is required.

Women of childbearing potential

Due to the long washout period of BYDUREON, women of childbearing potential should use contraception during treatment with BYDUREON. BYDUREON should be discontinued at least 3 months before a planned pregnancy.

Pregnancy

There are no adequate data from the use of BYDUREON in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. BYDUREON should not be used during pregnancy and the use of insulin is recommended.

Breastfeeding

It is unknown whether exenatide is excreted in human milk. BYDUREON should not be used during breast-feeding.

Fertility

No fertility studies in humans have been conducted.

No studies on the effects of the ability to drive and use machines have been performed. When BYDUREON is used in combination with a sulphonylurea, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines.

Summary of the safety profile

The most frequent adverse drug reactions ( 5 % of BYDUREON treatment) were mainly gastrointestinal related (nausea, vomiting, diarrhoea and constipation). The most frequently reported single adverse reaction was nausea which was associated with the initiation of treatment and decreased over time. In addition, injection site reactions (pruritus, nodules, erythema), hypoglycaemia (with a sulphonylurea), and headache occurred. Most adverse reactions associated with BYDUREON were mild to moderate in intensity.

Acute pancreatitis and acute renal failure have been reported rarely since exenatide twice daily has been marketed (see section 4.4).

Tabulated summary of adverse reactions

The frequency of adverse reactions of BYDUREON with an incidence of 1 % are summarised in Table 1 below.

The data source comprises two placebo controlled studies (10 and 15 weeks) and 3 trials comparing BYDUREON to either exenatide twice daily (a 30 week study), sitagliptin and pioglitazone (a 26 week study) and insulin glargine (a 26 week study). Background therapies included diet and exercise, metformin, a sulphonylurea, a thiazolidinedione or a combination of oral anti-diabetic agents.

The adverse reactions observed from post-marketing and clinical trial experience with exenatide twice daily that were not observed with BYDUREON at an incidence of 1 % are listed in Table 2 below.

The reactions are listed below as MedDRA preferred term by system organ class and absolute frequency. Patient frequencies are defined as: very common ( 1/10), common ( 1/100 to < 1/10), uncommon ( 1/1000 to < 1/100), rare ( 1/10000 to < 1/1000) and very rare (< 1/10000).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Table 1: The frequency of adverse reactions of BYDUREON with an incidence of 1 % in clinical trials. n= 592 total, (patients on sulphonylurea n= 135)

¹ Frequency of reactions was the same in the exenatide twice daily treatment group.

Table 2: The adverse reactions observed from post-marketing and clinical trial experience with exenatide twice daily that were not observed with BYDUREON at an incidence of 1 % are listed below:

¹ Rate based on exenatide twice daily clinical trial data.

² Rate based on exenatide twice daily spontaneous data.

³ Events were uncommon in all treatment groups.

Description of selected adverse reactions

Hypoglycaemia

The incidence of hypoglycaemia was increased when BYDUREON was used in combination with a sulphonylurea (15.9 % versus 2.2 %) (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).

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

Across all studies most episodes (96.8 % n=32) 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.

Nausea

The most frequently reported adverse reaction was nausea. In patients treated with BYDUREON, generally 20 % reported at least one episode of nausea compared to 34 % of exenatide twice daily 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 trial was 6 % for BYDUREON-treated patients, 5 % for exenatide twice daily-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 BYDUREON-treated patients and 1 % for exenatide twice daily-treated patients.

Injection site reactions

Injection site reactions were observed more frequently in BYDUREON-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.

Small subcutaneous injection site nodules were observed very frequently in clinical trials, 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 BYDUREON. 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 BYDUREON, approximately 45 % of patients had low titre antibodies to exenatide at study endpoint. Overall the percentage of antibody positive patients was consistent across clinical trials. Overall, the level of glycaemic control (HbA_1c) 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 BYDUREON was absent at the end of the controlled period of studies; 2.6 % of patients showed no glucose improvement with higher titre antibodies while 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.

For BYDUREON-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 BYDUREON-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).

Effects of overdoses with exenatide (based on exenatide twice daily 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.

Pharmacotherapeutic group: Drugs used in diabetes, other blood glucose lowering drugs, excl. Insulins. ATC code: A10BX04.

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, BYDUREON 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

The results of long term clinical studies of BYDUREON are presented below, these studies comprised 1628 subjects (804 treated with BYDUREON), 54 % men and 46 % women, 281 subjects (141 treated with BYDUREON) were 65 years of age.

Glycaemic control

In two studies BYDUREON 2 mg once weekly has been compared to exenatide twice daily 5 µg for 4 weeks followed by exenatide twice daily 10 µg. 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 BYDUREON 2 mg once weekly for a further 22 weeks (n= 243). In both studies, decreases in HbA_1c were evident in both treatment groups as early as the first post-treatment HbA_1c measurement (weeks 4 or 6).

BYDUREON resulted in a statistically significant reduction in HbA_1c compared to patients receiving exenatide twice daily (Table 3).

A clinically relevant effect of BYDUREON and exenatide twice daily-treated subjects was observed on HbA_1c, regardless of the background anti-diabetic therapy in both studies.

Clinically and statistically significantly more subjects on BYDUREON compared to exenatide twice daily patients achieved an HbA_1c reduction of 7 % or < 7 % in the two studies (p < 0.05 and p=< 0.0001 respectively).

Both BYDUREON and exenatide twice daily patients achieved a reduction in weight compared to baseline, although the difference between the two treatment arms was not significant.

Further reductions in HbA_1c and sustained weight loss were observed for at least 52 weeks in the patients completing both the controlled 30 week study and the uncontrolled study extension. The evaluable patients who switched from exenatide twice daily to BYDUREON (n= 121) achieved the same improvement in HbA_1c of -2.0 % , at the end of the 22 week extension compared to the initial baseline, as the patients treated with BYDUREON for 52 weeks.

Table 3: Results of two trials of BYDUREON versus exenatide twice daily in combination with diet and exercise alone, metformin and/or sulphonylurea and metformin and/or thiazolidinedione (intent to treat patients).

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

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

Table 4: Results of one 26 week trial of BYDUREON versus insulin glargine in combination with metformin and/or sulphonylurea (intent to treat patients).

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

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.

In a 26 week double blind study BYDUREON was compared to maximum daily doses of sitagliptin and pioglitazone in subjects also using metformin. All treatment groups had a significant reduction in HbA_1c compared to baseline. BYDUREON demonstrated superiority to both sitagliptin and pioglitazone with respect to change in HbA_1c from baseline.

BYDUREON demonstrated significantly greater weight reductions compared to sitagliptin. Patients on pioglitazone gained weight (Table 5).

Table 5: Results of one 26 week trial of BYDUREON versus sitagliptin and versus pioglitazone in combination with metformin (intent to treat patients).

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

Body weight

A reduction in body weight compared to baseline has been observed in all BYDUREON studies. This reduction in body weight was seen in patients treated with BYDUREON irrespective of the occurrence of nausea although the reduction was larger in the group with nausea (mean reduction - 2.9 kg to - 5.2 kg with nausea versus - 2.2 kg to -2.9 kg without nausea).

The proportion of patients who had both a reduction in weight and HbA_1c ranged from 70 to 79 % (the proportion of patients who had a reduction of HbA_1c ranged from 88 to 96 %).

Plasma/serum glucose

Treatment with BYDUREON resulted in significant reductions in fasting plasma/serum glucose concentrations, these reductions were observed as early as 4 weeks. 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 BYDUREON 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 BYDUREON studies (2.9 mmHg to 4.7 mmHg). In the 30 week exenatide twice daily comparator study both BYDUREON and exenatide twice daily 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.

Fasting lipids

BYDUREON has shown no adverse effects on lipid parameters.

Paediatric population

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

The absorption properties of exenatide reflect the extended release properties of the BYDUREON 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, 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 300 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 BYDUREON therapy, mean plasma exenatide concentrations fell below minimal detectable concentrations.

Special populations

Patients with renal impairment

Population pharmacokinetic analysis of renal impaired patients receiving 2 mg BYDUREON 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.

Patients with 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 exenatide twice daily in patients with type 2 diabetes, administration of exenatide (10 µg) 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 exenatide twice daily in 13 patients with type 2 diabetes and between the ages of 12 and 16 years, administration of exenatide (5 μg) resulted in slightly lower mean AUC (16 % lower) and C_max (25 % lower) compared to those observed in adults. No pharmacokinetics study of BYDUREON has been conducted in the paediatric population.

Non-clinical data reveal no special hazards for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, or genotoxicity conducted with exenatide twice daily or BYDUREON.

In a 104-week carcinogenicity study with BYDUREON a statistically significant increase in thyroid c - cell tumour incidence (adenomas and / or carcinomas) was observed in rats at all doses (1.4- to 26-fold the human clinical exposure with BYDUREON). The human 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.

Powder

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

sucrose

Solvent

carmellose sodium

sodium chloride

polysorbate 20

monobasic sodium phosphate, monohydrate

dibasic sodium phosphate, heptahydrate

water for injections

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

2 years

After reconstitution

The suspension must be injected immediately.

Store in a refrigerator (2ºC - 8ºC).

Do not freeze.

The kit may be kept for up to 4 weeks below 30ºC prior to use.

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

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

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

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

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

The patient should be instructed to discard the syringe safely, with the needle still attached after each injection. The patient should recap the needle. 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, BYDUREON should only be used if the mixture is white to off white and cloudy.

BYDUREON must be injected immediately after suspension of the powder in the solvent.

BYDUREON that has been frozen must not be used.

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

Eli Lilly Nederland B.V., Grootslag 1-5, NL-3991 RA Houten, The Netherlands.

17 June 2011

17 June 2011

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

POM