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 endstage 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 endstage 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 endstage 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, Dphenylalanine derivatives (meglitinides), alphaglucosidase 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