Consumer medicine information

Bydureon

Exenatide

BRAND INFORMATION

Brand name

Bydureon

Active ingredient

Exenatide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bydureon.

What is in this leaflet

This leaflet answers some common questions about BYDUREON.

It does not contain all the available information.

It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date shown on the final page. More recent information on this medicine may be available. Make sure you speak to your pharmacist, nurse or doctor to obtain the most up to date information on this medicine.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking BYDUREON against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, consult your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What BYDUREON is used for

BYDUREON is an injectable medicine used to improve blood sugar control in adults with type 2 diabetes mellitus.

BYDUREON is used with other medicines for type 2 diabetes mellitus when they are not enough to control your blood sugar level, along with diet and exercise.

Ask your doctor or healthcare professional if you are not sure whether your antidiabetic medicine contains sulfonylurea.

Diabetes mellitus is a condition in which your pancreas does not produce enough insulin to control your blood sugar level. BYDUREON helps your body to increase production of insulin when your blood sugar is high.

BYDUREON is not a substitute for insulin in patients who require insulin treatments for their diabetes.

This medicine has not been studied in children.

This medicine is only available with a doctor's prescription.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Before you use BYDUREON

When you must not use it

Do not use BYDUREON if:

  • you have type 1 diabetes or diabetic ketoacidosis (often caused by very high blood glucose levels)
  • you are allergic to exenatide or any of the ingredients listed at the end of this leaflet
  • you have severe kidney problems or you are on dialysis

Do not use BYDUREON after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

Return the product to your pharmacist if it has expired or is damaged.

Talk to your doctor if you are not sure whether you should start using BYDUREON.

Before you start to use it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you have or have had any of the following medical conditions:

  • kidney problems
  • high blood pressure or other heart problems
  • high cholesterol and triglycerides (a lipid disorder involving too many fatty acids in the blood stream)
  • pancreatitis
  • gall stones
  • inflammation of the gall bladder (cholecystitis)
  • alcohol abuse

Tell your doctor if you have severe problems with your stomach or food digestion. BYDUREON slows stomach emptying so food passes more slowly through your stomach.

Tell your doctor if you are pregnant or plan to become pregnant. Use of this medicine in pregnancy is limited. Your doctor can discuss with you the risks and benefits involved.

Tell your doctor if you are breast-feeding or plan to breast-feed. It is not known if this medicine passes into your breast milk. Your doctor can discuss with you the risks and benefits involved.

If you have not told your doctor about any of the above, tell them before you start using this medicine.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may be affected by BYDUREON or may affect how it works. You may need different amounts of your medicines or you may need to take different medicines.

These include:

  • warfarin, a medicine used to prevent blood clots. Taking BYDUREON while you are taking warfarin may cause you to bleed more easily
  • angiotensin converting enzyme inhibitors, medicines used to treat high blood pressure and other heart conditions
  • nonsteroidal anti-inflammatory medicines
  • diuretics, medicines used to treat fluid retention and high blood pressure. Taking BYDUREON while you are taking these medicines may affect your kidneys
  • orlistat, a weight loss medicine
  • opioids, a narcotic commonly used as a pain killer
  • anticholinergics, a type of medicine used to relieve stomach cramps or spasms, to treat travel sickness and to treat Parkinson's disease
  • when using BYDUREON in combination with sulfonylureas, you may need to adjust the dose of the sulfonylurea to avoid hypoglycaemia
  • use of BYDUREON with insulins or other GLP-1 receptor agonists (e.g. BYETTA) is not recommended

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

How to use BYDUREON

Carefully follow all the directions given to you by your doctor or health care professional. They may differ from the information contained in this leaflet.

How to use it

BYDUREON is supplied in three presentations:

  • BYDUREON kit - containing a vial and syringe
  • BYDUREON pre-filled pen
  • BYDUREON BCise autoinjector

Your healthcare professional should teach you how to use the BYDUREON kit, pen or autoinjector.

Remove the BYDUREON kit, pen or autoinjector from the refrigerator and rest it flat for at least 15 minutes prior to use.

BYDUREON kit and pen is provided as a powder that must be mixed with a diluent (solvent) before use. Only mix BYDUREON with the diluent if the diluent is clear and free of particles. Once you have mixed BYDUREON with the diluent, the mixture should be white to off -white, have no clumps and be uniformly cloudy.

BYDUREON kit or pen must be injected immediately after mixing with the diluent.

BYDUREON BCise autoinjector is provided as a suspension that should be white to off-white and cloudy. Mix the suspension by shaking hard for at least 15 seconds. Use the suspension only if it is evenly mixed.

If you see white medicine on the sides, bottom or top of the autoinjector window, the medicine is NOT mixed well. Shake hard again until mixed well.

BYDUREON BCise autoinjector must be injected immediately after mixing the suspension.

Read the User Manual for information on how to use the BYDUREON kit, pen or autoinjector before use.

Read the User Manual each time you get a new kit or pen, in case something has changed.

Refer to the User Manual each time you inject this medicine.

Use a new BYDUREON kit, pen or autoinjector for each injection and dispose of it after use.

This medicine is for you only. Never share BYDUREON with others.

If you do not understand the User Manual, ask your doctor or health care professional for help.

How much to use

Each BYDUREON kit, pen or autoinjector contains one dose, you should use the full dose each time you inject.

BYDUREON needs to be injected only once per week.

Use BYDUREON exactly as prescribed by your doctor.

When to use it

Inject BYDUREON once a week, at any time of the day, with or without meals.

You may wish to choose a specific day of the week that will be your BYDUREON injection day.

How long to use it

Do not stop using BYDUREON unless your doctor tells you to.

If you forget to use it

If you miss a dose of BYDUREON and there is at least 3 days until your next dose, you should take it as soon as you remember.

If you miss a dose of BYDUREON and there is 1 or 2 days until your next dose, you should wait until your next regularly scheduled dose to take it.

The next weekly dose can be taken on the preferred day of the week as long as it is at least 3 days after the last dose was taken.

Do not take an extra dose or increase the amount of your next dose to make up for the one you missed.

If you are not sure if you have taken your entire dose, do not inject another dose of BYDUREON. Wait until your next weekly dose is due.

Ask your healthcare professional if you are not sure what to do.

If you have trouble remembering to use your medicine, ask your doctor or healthcare professional for some hints.

If you take too much (overdose)

If you take too much BYDUREON, immediately call your doctor or the Poisons Information Centre (telephone AU: 13 11 26, NZ: 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital.

Symptoms of an overdose may include nausea, vomiting, dizziness, or symptoms of low blood sugar. You may need urgent medical attention.

While you are using BYDUREON

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using BYDUREON.

Tell any other doctors, dentists and health care professionals who treat you that you are using this medication.

If you are going to have surgery, tell the surgeon or anaesthetist that you are using this medicine. It may affect other medicines used during surgery.

If you become pregnant while using this medicine, tell your doctor immediately. Make sure all friends, relatives, workmates or carers know that you have diabetes.

Tell your doctor if you experience hypoglycaemia (low blood sugar levels).

When BYDUREON is used with a medicine that contains sulfonylurea, hypoglycaemia can occur. The dose of your sulfonylurea medicine may need to be reduced while you use BYDUREON.

Some symptoms of hypoglycaemia are:

  • drowsiness
  • weakness
  • confusion
  • irritability
  • hunger
  • fast heartbeat
  • sweating

If you are experiencing any of these symptoms of hypoglycaemia, immediately eat some sugary food or have a drink, e.g. lollies, biscuits or fruit juice.

Tell your doctor if you have trouble recognising the symptoms of hypoglycaemia. Under certain conditions, the early warning signs of hypoglycaemia can be different or less obvious.

Tell your doctor, diabetes education nurse or pharmacist if you are travelling. You may not be able to get BYDUREON in the country you are visiting.

Ask your doctor for a letter explaining why you are taking injecting devices with you. Each country you visit will need to see this letter, so you should take several copies.

Your doctor, diabetes education nurse or pharmacist can provide you with some helpful information.

Things you must not do

Do not stop using your medicine or change your dosage unless your doctor tells you to.

Do not use the medicine if you think it has been frozen or exposed to excessive heat. It will not work as it should.

Do not use this medicine to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Things to be careful of

Tell your doctor if you drink alcohol. Alcohol may mask the symptoms of hypoglycaemia, or make it worse.

Be careful driving or operating machinery.

If you use BYDUREON in combination with sulfonylureas, hypoglycaemia can occur. Hypoglycaemia may reduce your ability to concentrate.

Side effects

Tell your doctor or healthcare professional as soon as possible if you do not feel well while you are using BYDUREON.

BYDUREON helps most people with type 2 diabetes, but it may have unwanted side effects in some people. All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Ask your doctor or healthcare professional to answer any questions you may have.

When BYDUREON is used with a medicine that contains sulfonylurea, hypoglycaemia can occur.

Tell your doctor if you experience hypoglycaemia.

Tell your doctor if you experience worsening blood sugar control.

Tell your doctor if you notice any of the following:

  • nausea
  • vomiting
  • diarrhoea
  • constipation
  • dizziness or light headedness
  • headache
  • feeling jittery
  • acid stomach
  • abdominal pain or distension
  • loss of energy and strength
  • redness, swelling or itching at the injection site (local allergy)
  • a lump or hardening under the skin at the injection site
  • indigestion (dyspepsia)
  • excessive sweating (hyperhidrosis)
  • mood changes
  • flu-like symptoms
  • bone or muscle pain

These are the more common side effects of BYDUREON. Mostly these are mild and short-lived.

BYDUREON may reduce your appetite. Nausea and vomiting were very commonly reported in patients using BYDUREON. Mostly these were mild to moderate and short-lived. In most patients who initially experienced nausea, the frequency and severity decreased with continued therapy.

You may experience dehydration as a result of nausea, vomiting and/or diarrhoea. Some symptoms of mild to moderate dehydration are:

  • dry mouth
  • decreased frequency of urination and concentrated urine
  • headache
  • muscle weakness
  • dizziness or light headedness

Drink plenty of fluids if you are experiencing any of these symptoms. Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you continue to experience these symptoms.

Tell your doctor immediately if you notice any of the following:

  • passing little or no urine
  • taste disturbance or loss of taste
  • sleepiness or drowsiness
  • swelling of the face, lips, mouth, tongue or throat which may cause difficulty in swallowing or breathing
  • stomach discomfort relieved by belching or passing wind
  • constipation
  • itching
  • hives, pinkish, itchy swellings on the skin, itchy rash
  • red raised skin rash
  • serious skin reactions at the injection site, including ulcer, swollen cavity containing pus (abscess) or red area of skin that feels hot and tender (cellulitis)
  • bleeding more easily than normal, if you are taking warfarin

These are rare or very rare side effects of BYDUREON. The above list includes serious side effects which may require medical attention.

Tell your doctor immediately if you are experiencing any of the following:

  • severe abdominal pain and
  • vomiting and/or
  • diarrhoea and/or
  • nausea

These can be symptoms of acute pancreatitis which has been reported rarely in patients taking BYDUREON.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some people.

After using BYDUREON

Storage

Keep BYDUREON in the refrigerator where the temperature stays between 2-8°C. Do not freeze. Do not use BYDUREON if it has been frozen.

BYDUREON must be stored flat.

Keep this medicine where children cannot reach it.

Each BYDUREON kit, pen or autoinjector contains one dose, you should use the full dose each time you inject.

Use a new BYDUREON kit, pen or autoinjector for each injection and dispose of it after use.

BYDUREON can be kept out of the refrigerator (below 30°C) for a total of 4 weeks.

Discard the used BYDUREON components, including the needle, immediately after use.

Ask your pharmacist how to discard BYDUREON.

BYDUREON is for use in a single patient only.

Disposal

Dispose of your BYDUREON kit, pen or autoinjector with the needle still attached into a yellow plastic sharps container or similar puncture proof container composed of hard plastic or glass (the needle is hidden in the autoinjector).

Ask your doctor, nurse or pharmacist where you can dispose of the container when it is full.

If your doctor tells you to stop using this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

BYDUREON kit
BYDUREON powder is white to off-white. The diluent is a clear colourless to pale yellow to pale brown liquid. When mixed together, the solution is white to off-white and cloudy.

BYDUREON is supplied in a kit containing a vial of exenatide powder, a syringe of diluent (solvent), an adapter and 2 needles (1 spare). Each kit contains dosing for 1 week of treatment as a single dose.

BYDUREON kit is supplied in a pack of 4 single dose kits.

BYDUREON pen
BYDUREON powder is white to off-white. The diluent is a clear colourless to pale yellow to pale brown liquid. When mixed together, the solution is white to off-white and cloudy.

BYDUREON is supplied in a dual-chambered pen containing exenatide powder in one chamber and diluent (solvent) in the other chamber for suspension.

Each pre-filled pen is provided with one custom needle. Each pack also contains one spare needle.

Each pen contains dosing for 1 week of treatment as a single dose.

BYDUREON pen is supplied in a pack of either 4 single dose pens or 1 single dose pen.

BYDUREON BCise autoinjector
BYDUREON suspension is white to off-white and cloudy

BYDUREON is supplied in an autoinjector containing a suspension of exenatide.

Each autoinjector contains dosing for 1 week of treatment as a single dose.

BYDUREON BCise autoinjector is supplied in a pack of either 4 single dose autoinjectors or 1 single dose autoinjector.

Ingredients

BYDUREON powder contains 2 mg of exenatide as the active ingredient. It also contains polyglactin and sucrose.

The diluent contains:

  • carmellose sodium
  • sodium chloride
  • polysorbate 20
  • monobasic sodium phosphate monohydrate
  • dibasic sodium phosphate (as heptahydrate)
  • sodium hydroxide (pen only)
  • water for injection

BYDUREON BCise autoinjector - the suspension contains 2 mg of exenatide as the active ingredient. It also contains polyglactin, sucrose and medium chain triglycerides.

Suppliers

Supplied in Australia by

AstraZeneca Pty Ltd
ABN 54 009 682 311
66 Talavera Road
Macquarie Park NSW 2113

Supplied in New Zealand by

AstraZeneca Limited
Auckland

For all enquiries contact AstraZeneca by calling 1800 805 342 (Australia) or 09 306 5650 (New Zealand)

Australian Registration Numbers

The Australian Registration Numbers for BYDUREON are:

BYDUREON Kit - AUST R 175504

BYDUREON Pen - AUST R 235962

BYDUREON BCise autoinjector - AUST R 298869

Further information

Your food and exercise plan, along with your periodic blood sugar testing and scheduled A1C (also known as HbA1C) checks, will continue to be important in managing your diabetes while you are taking BYDUREON.

You can get more information about diabetes from:

Diabetes Australia

  • free call helpline 1300 136 588
  • www.diabetesaustralia.com.au

Diabetes New Zealand

  • toll free helpline 0800 342 238
  • www.diabetes.org.nz

This leaflet was updated in February 2019.

BYDUREON® is a registered trademark of the AstraZeneca group of companies.

Doc ID-002466050 V8.0

Published by MIMS April 2019

BRAND INFORMATION

Brand name

Bydureon

Active ingredient

Exenatide

Schedule

S4

 

1 Name of Medicine

Exenatide.

6.7 Physicochemical Properties

Chemical structure.

The active ingredient in Bydureon is exenatide. Exenatide is a 39-amino acid peptide amide. It has the empirical formula C184H282N50O60S and molecular weight of 4186.6 Daltons. The amino acid sequence for exenatide is shown below.
H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

CAS number.

The CAS number for exenatide is 141732-76-5.

2 Qualitative and Quantitative Composition

Bydureon BCise suspension for injection in autoinjector (Bydureon BCise autoinjector).

Each autoinjector delivers a dose of 2 mg of exenatide in 0.85 mL.

Bydureon powder for injection in pre-filled pen (Bydureon pen).

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

Bydureon powder for injection in vial with diluent syringe (Bydureon kit).

Each vial contains 2 mg of exenatide. After suspension, a dose of 2 mg in 0.65 mL is delivered.
Bydureon is an extended release microspheres formulation of exenatide. When the product is prepared as instructed, the resulting suspension contains 2 mg exenatide. The suspension is intended for subcutaneous use only, once per week.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Bydureon is supplied in the following presentations:

Bydureon BCise autoinjector.

Extended-release suspension for injection.
White to off-white opaque suspension.

Bydureon pen.

Powder and diluent for extended-release suspension for injection.
Powder. White to off-white powder.
Diluent. Clear, colourless to pale yellow to pale brown solution.

Bydureon kit.

Powder and diluent for extended-release suspension for injection.
Powder. White to off-white powder.
Diluent. Clear, colourless to pale yellow to pale brown solution.
Exenatide is also available in an immediate-release formulation (Byetta). For information related to this formulation, please refer to the Byetta Product Information.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

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. This leads to an increase in both the glucose dependent insulin synthesis and secretion from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signalling pathways. As blood glucose concentrations decrease, insulin secretion subsides thereby reducing the potential risk of hypoglycaemia. When exenatide was used in combination with metformin, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin which may be due to this glucose dependent insulinotropic mechanism.
Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in 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.

Pharmacodynamic effects.

Exenatide improves glycaemic control through the immediate and sustained effects of lowering both postprandial and fasting glucose concentrations in patients with type 2 diabetes. These pharmacodynamic actions occur through various mechanisms including stimulation of insulin secretion during hyperglycaemia, suppression of glucagon, and slowing of gastric emptying. 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.

Glucose dependent insulin secretion.

Exenatide has acute effects on pancreatic beta cell responsiveness to glucose leading to insulin release predominantly in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycaemia. Exenatide does not impair the normal glucagon response to hypoglycaemia.

First phase insulin response.

In healthy individuals, robust insulin secretion occurs during the first 10 minutes following intravenous (IV) glucose administration. This secretion, known as the first phase insulin response, is characteristically absent in patients with type 2 diabetes. The loss of the first phase insulin response is an early beta cell defect in type 2 diabetes. Administration of exenatide at therapeutic plasma concentrations restored first phase insulin response to an IV bolus of glucose in patients with type 2 diabetes (see Figure 1). Both first phase insulin secretion and second phase insulin secretion were significantly increased in patients with type 2 diabetes treated with exenatide compared with saline (p < 0.001 for both).

Glucagon secretion.

In patients with type 2 diabetes, exenatide moderates glucagon secretion and lowers serum glucagon concentrations during periods of hyperglycaemia. Lower glucagon concentrations lead to decreased hepatic glucose output and decreased insulin demand.

Beta cell function.

Exenatide stimulates insulin release. Clinical trial data with exenatide twice daily show that this happens acutely with benefits in glycosylated haemoglobin evident within six weeks. No clinical data are available to suggest an improvement over time in beta cell function. In studies of exenatide twice daily, most clinical benefit in glycaemic control was seen within 12 weeks of commencement. An increase in pancreatic islet cell mass has not been consistently demonstrated in animal models.

Clinical trials.

Both improvement of glycaemic control and reduction of cardiovascular morbidity and mortality are an integral part of the treatment of type 2 diabetes.

Bydureon kit and pen.

Patients with type 2 diabetes participated in 4 long-term, randomised, comparator controlled, clinical studies of 2 mg exenatide once weekly up to 52 weeks duration (3 studies were open label and 1 was double blind). These studies were conducted to evaluate the efficacy and safety of 2 mg exenatide once weekly compared to either 10 microgram exenatide twice daily, insulin glargine once daily, or pioglitazone or sitagliptin once daily, in both treatment naive patients and those on background therapy with metformin and/or sulfonylurea and/or thiazolidinedione. A total of 1628 patients were included across the 5 studies, 804 of which were treated with 2 mg exenatide once weekly, 54% of all study participants were men and 141 patients treated with 2 mg exenatide once weekly were ≥ 65 years of age.
In addition, a double blind, placebo controlled cardiovascular outcome study (EXSCEL) enrolled 14,752 subjects with type 2 diabetes and any level of CV risk when added to the current usual care.

Glycaemic control.

In 24 week and 30 week clinical trials, 2 mg exenatide once weekly was compared to 5 microgram exenatide twice daily for 4 weeks followed by 10 microgram exenatide twice daily (see Section 5.2 Pharmacokinetic Properties, Absorption for information on relative systemic exposures). A 22 week open labelled extension period followed the 30 week study where all patients were treated with 2 mg exenatide once weekly. In both studies, decreases in HbA1c were evident in both treatment groups as early as the first post-treatment HbA1c measurement (weeks 4 or 6).
Exenatide once weekly resulted in a statistically significant reduction in HbA1c compared to patients receiving exenatide twice daily, p < 0.0001 in the 24 weeks study and p < 0.05 in the 30 weeks study respectively.
A consistently positive effect of exenatide once weekly and twice daily treated subjects was observed on HbA1c, regardless of the background antidiabetic therapy in both studies.
In a 26 week study 2 mg exenatide once weekly was compared to insulin glargine once daily. Both treatment groups had a significant reduction in HbA1c, (p < 0.001) while exenatide once weekly demonstrated a superior change in HbA1c compared to insulin glargine (p = 0.017).
In a 26 week double blind study, 2 mg exenatide once weekly was compared to maximum daily doses of sitagliptin and pioglitazone in subjects also using maximal or near maximal doses of metformin. All treatment groups had a significant reduction in HbA1c compared to baseline. Exenatide once weekly demonstrated superiority to both sitagliptin (p < 0.00001) and pioglitazone (p = 0.0165) with respect to change in HbA1c from baseline.
Table 4 shows HbA1c results for each of the comparator controlled studies. See Figure 2.
Further reductions in HbA1c were observed for at least 52 weeks in the patients completing both the 22 week uncontrolled study extension. The evaluable patients who switched from exenatide twice daily to 2 mg exenatide once weekly (n = 121) achieved the same improvement in HbA1c of -2.0%, at the end of the extension period compared to the initial baseline, as the patients treated with 2 mg exenatide once weekly for 52 weeks.

Proportion of patients achieving target.

As shown in Table 5, clinically and statistically significantly more patients on 2 mg exenatide once weekly compared to exenatide twice daily patients achieved an HbA1c reduction of ≤ 7% or < 7% in the 24 week and 30 week studies (p < 0.0001 and p < 0.05 respectively). Significantly more patients on 2 mg exenatide once weekly achieved an HbA1c reduction of ≤ 7% compared to those receiving 100 mg sitagliptin (p < 0.0001) and 45 mg pioglitazone (p < 0.05).

Bodyweight.

A reduction in bodyweight compared to baseline has been observed in all 2 mg exenatide once weekly studies. This reduction in bodyweight was seen in patients treated with 2 mg exenatide once weekly 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 versus -2.2 kg to -2.9 kg).
In studies comparing 2 mg exenatide once weekly to 10 microgram exenatide twice daily, both treatment arms achieved a reduction in bodyweight from baseline, although the difference in the treatment groups was not significant.
When compared with insulin glargine treatment, 2 mg exenatide once weekly treatment significantly lowered mean bodyweight (p < 0.001) and was associated with fewer hypoglycaemic events. Significantly greater weight reduction was also achieved compared to sitagliptin (p = 0.0002). Patients on pioglitazone gained weight (p < 0.0001) (see Table 6).
The proportion of patients who had a reduction of HbA1c ranged from 89 to 96%, 70 to 79% of patients had a reduction in HbA1c and weight.

Plasma/ serum glucose.

Treatment with 2 mg exenatide once weekly 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.

Fasting lipids.

Bydureon did not have adverse effects on lipid parameters.

Patient outcomes.

Exenatide once weekly consistently improved patient satisfaction as measured by the diabetes treatment satisfaction questionnaires.

Concomitant initiation of exenatide once weekly and dapagliflozin vs. exenatide once weekly alone and dapagliflozin alone, as add-on to metformin.

A 28-week, double-blind, active-controlled trial was conducted to evaluate the efficacy and safety of exenatide 2 mg once weekly and dapagliflozin 10 mg once daily (SGLT2 inhibitor), when initiated concomitantly, versus exenatide 2 mg once weekly alone and dapagliflozin 10 mg once daily alone, in a total of 694 patients with type 2 diabetes who were not achieving adequate glycaemic control on a background of metformin (≥ 1500 mg/day).
All patients entered a 1-week placebo lead-in period. Patients with HbA1c ≥ 8.0 and ≤ 12.0% were randomly assigned to receive exenatide once weekly and dapagliflozin 10 mg once daily, exenatide 2 mg once weekly alone or dapagliflozin 10 mg once daily alone. During the treatment period, patients continued on the same type and dose of metformin as when they entered the study. Randomisation was stratified by HbA1c at baseline (< 9.0% or ≥ 9.0%) and patients were regularly monitored every 4 weeks in this study.
The majority of patients (84%) were White, 14% Black or African, 2% Other and < 1% Asian and American Indian or Alaska Native.
At baseline, patients had a mean age of 54.2 years and a BMI of 32.73 kg/m2. The primary endpoint was the change in HbA1c from baseline to Week 28 (Figure 3). Compared to exenatide 2 mg once weekly alone and dapagliflozin 10 mg once daily alone, concomitant initiation of exenatide 2 mg once weekly and dapagliflozin 10 mg once daily resulted in statistically significant reductions in HbA1c from baseline at Week 28 (Table 7).
Compared to exenatide once weekly alone, concomitant use of exenatide once weekly and dapagliflozin 10 mg, resulted in significantly greater reductions in fasting plasma glucose from baseline at Week 2 (-2.3 mmol/L with exenatide once weekly + dapagliflozin vs. -1.2 mmol/L with exenatide once weekly + placebo, p < 0.001).

Exenatide 2 mg once weekly vs. placebo as add-on to basal insulin alone or in combination with metformin.

A 28-week, double-blind, placebo-controlled trial was conducted to evaluate the efficacy and safety of exenatide 2 mg once weekly (n=231) versus placebo (n=230) when added to titrated basal insulin glargine, with or without metformin, in patients with type 2 diabetes with inadequate glycaemic control.
All patients initially entered an 8-week insulin dose optimisation phase. Patients on sulfonylurea therapy discontinued sulfonylurea. The dose of insulin glargine was titrated to a target fasting plasma glucose of 4.0 to 5.5 mmol/L. Patients with HbA1c ≥ 7.0% and ≤ 10.5% were then randomly assigned to receive either exenatide 2 mg once weekly or placebo. Insulin glargine dose titration continued throughout the treatment phase of the study. Patients who had been on metformin at baseline (≥ 1,500 mg/day) continued on the same type and dose of metformin therapy throughout the study.
The majority of the patients (87%) were White, 10% Black or African American, 1% Asian, 1% Other, < 1% American Indian or Alaska Native, and < 1% Pacific Islander.
At baseline, patients had a mean age of 57.7 years, a mean BMI of 33.66 kg/m2, a mean diabetes duration of 11.29 years and a mean HbA1c of 8.53%. The primary endpoint was the change in HbA1c from baseline to Week 28 (Figure 4). Exenatide 2 mg once weekly achieved a significantly greater reduction in HbA1c at Week 28 than that observed with placebo (Table 8).
The mean daily insulin dose was increased from baseline to Week 28 for both treatment groups (50.4 to 51.9 units in the exenatide 2 mg once weekly group and 51.0 to 54.2 units in the placebo group). The difference in change from baseline to Week 28 in mean daily insulin dose was not statistically significant (-2.0 units, p=0.068).
Larger proportions of patients in the exenatide 2 mg once weekly group (22%) achieved HbA1c < 7.0% at Week 28 with no weight gain and no major hypoglycaemia over 28 weeks compared to the placebo group (3%).

Cardiovascular outcomes.

EXSCEL was a multinational, placebo-controlled, double-blind, randomised, parallel group pragmatic study that evaluated cardiovascular (CV) outcomes during treatment with exenatide 2 mg once weekly in patients with type 2 diabetes and any level of CV risk when added to the current usual care.
A total of 14,752 patients were randomised 1:1 to either exenatide 2 mg once weekly or placebo and followed as in routine clinical practice for a median of 38.7 months with a median treatment duration of 27.8 months. Ninety six percent of the patients in both treatment groups completed the study in accordance with the protocol, and the vital status was known at the end of the study for 98.9% and 98.8% of the patients in the 2 mg exenatide once weekly and placebo group, respectively. The demographics and baseline characteristics were well-balanced between treatment groups.
The mean age at study entry was 62 years (21 to 92 years with 8.5% of the patients ≥ 75 years). Approximately 62.0% of the patients were male, 75.8% were Caucasian, 9.8% were Asian, 6.0% were Black, and 20.5% were Hispanic or Latino. The mean BMI was 32.7 kg/m2 and the mean duration of diabetes was 13.1 years. Approximately 49.3% had mild renal impairment (estimated glomerular filtration rate [eGFR] ≥ 60 to ≤ 89 mL/min/1.73 m2) and 21.6% had moderate renal impairment (eGFR ≥ 30 to ≤ 59 mL/min/1.73 m2).
The mean HbA1c was 8.1%. At baseline, 1.5% of patients were not treated with either oral antidiabetic medications or insulin, 42.3% were treated with one oral antidiabetic medication and 42.4% were treated with two or more oral antidiabetic medications. Usage of oral antidiabetic medications included metformin (76.6%), sulfonylurea (36.6%), DPP-4 inhibitors (14.9%), thiazolidinediones (3.9%), and SGLT-2 inhibitors (0.9%).
Overall insulin usage was 46.3% (13.8% with insulin alone and 32.6% with insulin and one or more oral antidiabetic medications). Overall, 26.9% of patients did not have any prior cardiovascular (CV) event, 73.1% had at least one prior CV event. The concomitant use of CV medications (e.g. ACE inhibitors, angiotensin receptor blockers, diuretics, beta blockers, calcium channel blockers, antithrombotic and anticoagulants, and lipid-lowering agents) was similar in the exenatide 2 mg once weekly and placebo groups. At baseline, the mean systolic blood pressure was 135.5 mmHg, the mean diastolic blood pressure was 78.1 mmHg, the mean LDL was 2.5 mmol/L, and the mean HDL was 1.1 mmol/L.
The primary endpoint in EXSCEL was the time to first confirmed Major Adverse Cardiac Event (MACE). A major adverse cardiac event was defined as occurrence of either a cardiovascular (CV)-related death, or a nonfatal myocardial infarction (MI) or a nonfatal stroke. All-cause mortality, CV-related death, and fatal or nonfatal MI or stroke, hospitalisation for acute coronary syndrome, and hospitalisation for heart failure were also assessed as secondary endpoints.
A Cox proportional hazards model was used to test for non-inferiority against the pre-specified risk margin of 1.3 for the hazard ratio of MACE and superiority on MACE if non-inferiority was demonstrated. Type-1 error was controlled across multiples tests using a hierarchical testing strategy.
Exenatide 2 mg once weekly did not increase the risk of MACE in patients with type 2 diabetes mellitus compared to placebo when added to current usual care (HR: 0.91; 95% CI: 0.832, 1.004; P < 0.001 for non-inferiority (safety hypothesis); and did not reach statistical significance for superiority (P=0.061) (efficacy hypothesis)). The results for the primary composite endpoint are shown in Figure 5.
The incidence of MACE in patients with and without established CV disease was 13.4% in the exenatide 2 mg once weekly group versus 14.6% in the placebo group, and 6.0% (exenatide) versus 5.9% (placebo), respectively. The results for the primary composite components and secondary cardiovascular endpoints are shown in Figure 6.

Bydureon BCise autoinjector.

Exenatide 2 mg once weekly suspension in autoinjector vs. exenatide 10 mcg twice daily as add on to diet and exercise alone or in combination with one or any two of metformin, sulfonylurea, or thiazolidinedione.

A 28-week, open-label comparator-controlled trial with a 24 week open ended extension period was conducted to evaluate the efficacy and safety of exenatide 2 mg once weekly suspension in autoinjector (n=229) versus exenatide 10 mcg twice daily (n=146) in patients with type 2 diabetes who were not achieving adequate glycaemic control on diet and exercise alone, or in combination with a stable regimen of oral antidiabetic medication (one or any two of metformin, sulfonylurea or thiazolidinedione).
All patients were randomly assigned to receive either exenatide 2 mg once weekly suspension in autoinjector or exenatide 10 mcg twice daily. Patients assigned to exenatide 10 mcg twice daily initiated treatment with 5 mcg twice daily for 4 weeks, followed by 10 mcg twice daily for 24 weeks, followed by a switch to exenatide 2 mg once weekly suspension in autoinjector for 24 weeks.
The majority of the patients (74%) were Caucasian, 16% Black or African American, 7% Asian, 1% listed as other, 1% American Indian or Alaska Native, and < 1% Native Hawaiian or other Pacific Islander.
The primary endpoint was change in HbA1c from baseline to Week 28 (Figure 7). Exenatide 2 mg once weekly suspension in autoinjector achieved a statistically significantly larger reduction in HbA1c than that observed with exenatide 10 mcg twice daily (Table 9).
The effects in HbA1c at Week 52 converged for both groups and appeared to reach a plateau. The LS mean change from baseline (SE) was-1.00% (0.11%) and -0.99% (0.13%) in the exenatide 2 mg once weekly suspension in autoinjector and exenatide twice daily treatment groups, respectively.

Exenatide 2 mg once weekly suspension in autoinjector vs. sitagliptin or placebo as add-on to metformin.

A 28-week, open-label (oral medication blinded), comparator- and placebo-controlled trial was conducted to evaluate the efficacy and safety of exenatide 2 mg once weekly suspension in autoinjector (n=181) versus sitagliptin (n=122) and placebo (n=61) in patients with type 2 diabetes who were not achieving adequate glycemic control with ≥ 1500 mg metformin daily.
All patients were randomly assigned to receive either exenatide 2 mg suspension once weekly in autoinjector, sitagliptin once daily or placebo once daily.
The majority of the patients (81%) were Caucasian, 14% Black or African American, 4% Asian and < 1% American Indian or Alaska Native, and Native Hawaiian or other Pacific Islander.
The primary endpoint was change in HbA1c from baseline to Week 28 (Figure 8). Exenatide 2 mg once weekly suspension in autoinjector achieved a statistically significantly larger reduction in HbA1c than that observed with sitagliptin and placebo (Table 10).

5.2 Pharmacokinetic Properties

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.

Bydureon kit and pen.

A single dose of Bydureon exhibits multiphasic release over an approximately 10 week period. This is interpretable as an initial period involving the release of surface bound exenatide followed by 2 subsequent peaks representing the hydration and erosion of the microspheres. However, there are significant interindividual variations in release as shown in terms of mean (see Figure 9, top and middle) and individual plasma levels (see Figure 9, bottom) reflecting large inherent variability in release from the dose form.
Following weekly administration of 2 mg exenatide once weekly to patients with type 2 diabetes, mean drug concentrations exceeded minimal efficacious concentrations (~ 50 picogram/mL) in 2 weeks with gradual increase in the average plasma exenatide concentration over 6 to 7 weeks. Subsequently, exenatide concentrations of approximately 300 picogram/mL were maintained indicating that steady state was achieved.
Steady-state drug concentrations are maintained during the one week interval between doses with minimal peak to trough fluctuation from this average therapeutic concentration. The bioavailability of Bydureon was approximately 25% (i.e. systemic exposure is 500 microgram per week) compared with the immediate release formulation, Byetta at 10 microgram twice daily, which gives an exposure of 140 microgram/week.

Bydureon BCise autoinjector.

Following weekly administration of 2 mg exenatide once weekly suspension in autoinjector, mean drug concentrations exceeded minimal efficacious concentrations (~ 50 picogram/mL) in 2 weeks with gradual increase in the average plasma exenatide concentration up to week 8. Subsequently, exenatide concentrations of approximately 208 picogram/mL were maintained indicating that steady-state was achieved.

Distribution.

The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of exenatide is 28.3 L.

Metabolism.

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtration with subsequent proteolytic degradation.

Excretion.

The mean apparent clearance of exenatide in humans is 9.1 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose. Approximately 10 weeks after discontinuation of exenatide once weekly therapy, mean plasma exenatide concentrations fell below minimal detectable concentrations.

Special populations.

Patients with renal impairment.

No clinically meaningful differences were observed in steady state exenatide concentrations or tolerability in patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min) compared to those with normal renal function. No dosage adjustment of Bydureon is required for patients with mild to moderate renal impairment. Bydureon is not recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min) or for patients with endstage renal disease receiving dialysis (see Section 4.2 Dose and Method of Administration; Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

Patients with hepatic insufficiency.

No pharmacokinetic study has been performed in patients with a diagnosis of acute or chronic hepatic insufficiency. Exenatide is cleared primarily by the kidney; therefore hepatic dysfunction is not expected to affect blood concentrations of exenatide.

Gender, race and bodyweight.

Gender, race and bodyweight 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 Byetta 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 Dose and Method of Administration).

5.3 Preclinical Safety Data

Genotoxicity.

Exenatide was not genotoxic in bacterial reverse mutation assays, in vitro chromosomal aberration tests in Chinese hamster ovary cells or a mouse micronucleus assay.

Carcinogenicity.

See Section 4.4 Special Warnings and Precautions for Use.

4 Clinical Particulars

4.1 Therapeutic Indications

Bydureon is indicated for the treatment of type 2 diabetes mellitus to improve glycaemic control in combination with other glucose-lowering medicinal products when the therapy in use, together with diet and exercise, does not provide adequate glycaemic control (see Section 5.1 Pharmacodynamic Properties, Clinical trials for available data on different combinations).

4.3 Contraindications

Bydureon is contraindicated in patients with known hypersensitivity to this product or any of its components (see Section 6.1 List of Excipients).
Bydureon should not be used in patients with endstage renal disease or severe renal impairment (creatinine clearance < 30 mL/min). Compared with healthy subjects, renal clearance of exenatide was significantly reduced in patients with endstage renal disease receiving dialysis, resulting in poor gastrointestinal tolerability.

4.4 Special Warnings and Precautions for Use

General.

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.
Bydureon has not been studied in patients with severe gastrointestinal disease, including gastroparesis. Its use is commonly associated with gastrointestinal adverse effects, including nausea, vomiting, and diarrhoea. Therefore, the use of Bydureon is not recommended in patients with severe gastrointestinal disease including gastroparesis and dumping syndrome.
The concurrent use of Bydureon with prandial insulin, D-phenylalanine derivatives, meglitinides, alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors ("gliptins"), orlistat, opioids, and anticholinergics has not been studied. The concomitant use of Bydureon and other GLP-1 receptor agonists is not recommended (see Section 4.2 Dose and Method of Administration).

Hypoglycaemia.

As would be expected for a blood glucose lowering agent, when exenatide was used in combination with a sulfonylurea; the incidence of hypoglycaemia was increased over that of placebo in combination with a sulfonylurea. In the clinical studies including patients on a sulfonylurea combination, those 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 sulfonylurea, reduction in the dose of sulfonylurea may be considered (see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects)).
Exenatide did not alter the counter-regulatory hormone response to insulin induced hypoglycaemia in a randomised, double blind, controlled study in healthy subjects.

Interaction with warfarin.

Since market introduction there have been some spontaneously reported cases of increased INR (international normalized ratio) with concomitant use of warfarin and exenatide, sometimes associated with bleeding (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects), Spontaneous data).

Altered renal function.

There have been rare, spontaneously reported events of acute renal failure, worsened chronic renal failure, renal impairment, or increased serum creatinine among patients using exenatide. These events mostly occurred in patients also receiving one or more pharmacologic agents known to potentially affect renal function or hydration status and/or experiencing events of nausea, vomiting, diarrhoea, and/or dehydration. Concomitant agents included angiotensin converting enzyme inhibitors, nonsteroidal anti-inflammatory drugs, and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative agents, including exenatide (see Section 4.8 Adverse Effects (Undesirable Effects), Spontaneous data).

Pancreatitis.

Recognised risk factors for pancreatitis include a past history of pancreatitis, gallstones, alcoholism and severe hypertriglyceridaemia. Clinical judgement should be exercised when selecting antidiabetic treatments, including Bydureon, for these patients. The change in risk of recurrent pancreatitis in patients with a past history of pancreatitis who receive Bydureon is not known. There have been rare, spontaneously reported events of acute pancreatitis, including fatal cases of haemorrhagic or necrotising pancreatitis in patients who have received Byetta. Cases of haemorrhagic or necrotising pancreatitis have been reported across the adult age range (18 years and over, including the elderly). There are no early signs or symptoms that distinguish cases that will become acute haemorrhagic or necrotising pancreatitis from the less severe form of pancreatitis. This potential should be considered in patients treated with Bydureon who manifest symptoms and signs suggestive of pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Patients and their caregivers should be advised to report immediately to their doctor such abdominal pain particularly if associated with vomiting or diarrhoea. Generally, resolution of pancreatitis has been observed with supportive treatment. If pancreatitis is suspected, exenatide and other potentially suspect medications should be discontinued and not recommenced unless pancreatitis has been excluded.

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.

Injection site reactions.

There have been postmarket reports of serious injection site reactions, including abscesses, cellulitis, ulcers and necrosis.

Immunogenicity.

Patients may develop antibodies to exenatide. If there is worsening glycaemic control or failure to achieve target glycaemic control, alternative antidiabetic therapy should be considered (see Section 4.8 Adverse Effects (Undesirable Effects)).

Use in renal impairment.

No clinically meaningful differences were observed in steady state exenatide concentrations or tolerability in patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min) compared to those with normal renal function.
No dosage adjustment of Bydureon is required for patients with mild to moderate renal impairment. Bydureon is not recommended for patients with severe renal impairment (creatinine clearance < 30 mL/min) or for patients with endstage renal disease receiving dialysis (see Section 4.3 Contraindications).

Use in the elderly.

Population pharmacokinetic analysis of patients ranging from 22 to 73 years of age suggests that age does not influence the pharmacokinetic properties of exenatide (see Section 5.1 Pharmacodynamic Properties). In the 30 week and 26 week trials, Bydureon was studied in 46 patients and Byetta in 24 patients, who were at least 65 years old. In separate trials, Byetta was studied in 282 patients at least 65 years old, and in 16 patients at least 75 years old. No differences in safety or effectiveness were observed between these patients and younger patients. In a large cardiovascular outcomes trial, 2 mg exenatide once weekly was studied in 2,959 patients (40.3%) who were at least 65 years old and of those, 605 patients (8.2%) were at least 75 years old. Similar results were observed between the 2 mg exenatide once weekly and placebo groups with respect to safety outcomes. Because elderly patients are more likely to have decreased renal function, care should be taken when initiating Bydureon in the elderly based on renal function.

Paediatric use.

The safety and effectiveness of exenatide has not been established in children under 18 years of age.

Effects on laboratory tests.

No data available.

Carcinogenicity.

In a 104 week carcinogenicity study with the extended release formulation of exenatide, a statistically significant increase in thyroid c-cell tumour incidence (adenomas and / or carcinomas) was observed in rats at all doses (0.3 to 3 mg/kg/fortnight subcutaneously; 1.4 to 26 fold the human clinical exposure with exenatide once weekly). The available evidence indicates that these tumours are mediated by a specific GLP-1 receptor mechanism to which rodents are particularly sensitive. The human relevance of these findings is currently unknown but predicted to be low.

4.5 Interactions with Other Medicines and Other Forms of Interactions

The results of a study using paracetamol as a marker of gastric emptying suggest that the effect of Bydureon to slow gastric emptying is not expected to cause clinically significant relevant changes in Cmax or AUC of concomitantly administered oral medicines. Therefore, no dose adjustments of oral medicines are necessary when used concomitantly with Bydureon. However, the dose of a sulfonylurea may require adjustment due to the increased risk of hypoglycaemia associated with sulfonylurea therapy (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use, Hypoglycaemia).

Paracetamol.

Paracetamol was used as a model medicinal product to evaluate the effect of exenatide on gastric emptying.
When 1000 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 Cmax decreased by 16% (fasting) and 5% (fed) and Tmax was increased from approximately 1 hour in the control period to 1.4 hours (fasting) and 1.3 hours (fed). In the same study, when paracetamol was administered with a meal 15 minutes after Byetta, AUC and Cmax decreased by 20% and 21% respectively, and Tmax increased to 2 hours. Given that concomitant Bydureon administration with oral paracetamol, a marker of gastric emptying, did not alter AUC and resulted in a minor reduction in Cmax, no dosage adjustments are recommended with concomitant oral drugs, except when used with a sulfonylurea.
The following interaction studies have been conducted using Byetta but not Bydureon.

HMG-CoA reductase inhibitors.

The AUC and Cmax of lovastatin, a HMG-CoA reductase inhibitor, were decreased approximately 40% and 28%, respectively, and Tmax was delayed by about 4 h when Byetta was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In Byetta 30 week placebo controlled clinical trials, concomitant use of exenatide and HMG-CoA reductase inhibitors was not associated with consistent changes in lipid profiles. No predetermined dose adjustment is required; however lipid profiles should be monitored as appropriate.

Warfarin.

In a controlled clinical pharmacology study in healthy volunteers, a delay in warfarin Tmax of about 2 h was observed when warfarin was administered 35 min after Byetta. No clinically relevant effects on Cmax or AUC were observed (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects), Spontaneous data). INR should be monitored during initiation of Bydureon therapy in patients on warfarin and/or coumarol derivatives (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects), Spontaneous data).

Digoxin and lisinopril.

In interaction studies of the effect of Byetta on digoxin and lisinopril there were no clinical relevant effects on Cmax or AUC, however a delay in Tmax of about 2 h was observed.

Ethinyl estradiol and levonorgestrel.

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

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Animal studies did not indicate direct harmful effects with respect to fertility. Male and female fertility were unaffected in mice treated with exenatide at SC doses up to 760 microgram/kg/day, almost 150 times the clinical exposure at 2 mg/week based on AUC.
No fertility studies in humans have been conducted.
(Category C)
Bydureon is not recommended for use during pregnancy. No specific studies have been conducted in pregnant women.
Data on a limited number of exposed pregnancies indicate no adverse effects of exenatide on pregnancy or on the health of the foetus/ newborn child. To date, no other relevant epidemiological data are available.
Potential embryofetal effects were assessed with SC doses of exenatide during organogenesis in mice at 6, 68 and 760 microgram/kg/day and in rabbits at 0.2, 2, 22, 156 and 260 microgram/kg/day, giving respective exposures approximately 1.2, 8.6 and 148 times (mouse) and 0.1, 1.7, 79, 545 and 1323 times (rabbit) the clinical exposure at 2 mg/week. A low incidence of abortions and decreased fetal growth occurred in mice and rabbits at ≥ 68 and 22 microgram/day, respectively, which also caused a decrease in food consumption and bodyweight gain in dams. Alterations of skeletal ossification were observed in rabbits at ≥ 2 microgram/kg/day as a result of decreased food intake. Wavy ribs were seen in mice at 760 microgram/kg/day. Fetal umbilical hernias were increased in rabbits at ≥ 22 microgram/kg/day. There was minimal placental transfer of exenatide in animal studies in vivo or in human placental tissues in vitro. The fetal findings were probably secondary to effects on the dam.
High doses of exenatide administered to mice during gestation and lactation caused stillbirths, an increase in neonatal deaths and a decrease in neonatal growth at exposures almost 150 times the clinical exposure at 2 mg/week. The no observable effect level for perineonatal effects was 68 microgram/kg/day, giving exposures 18 times the clinical exposure.
It is unknown whether exenatide is excreted in human milk. In lactating mice given high doses of exenatide, low concentrations of exenatide were detected in milk (2.5% of plasma level). Neonatal deaths were increased in lactating mice at high doses (see Section 4.6 Fertility, Pregnancy and Lactation, Use in pregnancy). Bydureon should be administered to nursing women only if the potential benefit to the mother justifies the potential risk to the infant.

4.8 Adverse Effects (Undesirable Effects)

Summary of the safety profile.

The most common adverse reactions ≥ 5% of exenatide treatment were gastrointestinal related (nausea, vomiting, diarrhoea and constipation). The most frequently reported adverse reaction was nausea which was associated with the initiation of treatment and decreased over time. In addition, injection site pruritis, hypoglycaemia and headache were common. Most adverse reactions associated with exenatide were mild to moderate in intensity.
Acute pancreatitis and acute renal failure have been reported rarely since exenatide has been marketed (see Section 4.4 Special Warnings and Precautions for Use).

Tabulated summary of adverse reactions.

Bydureon kit and pen.

The frequency of adverse reactions of 2 mg exenatide once weekly and 10 microgram exenatide twice daily with an incidence of ≥ 2% are summarised in Table 1.
The tabulation summarises event data from 5 trials comparing 2 mg exenatide once weekly to either 10 microgram 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 sulfonylurea or a combination of oral antidiabetic agents.

Bydureon BCise autoinjector.

The frequency of adverse effects of 2 mg exenatide once weekly suspension in autoinjector with an incidence of ≥ 2% are summarised in the table below (Table 2).
The tabulation summarises event data from 2 trials (both 28 weeks duration) comparing exenatide 2 mg once weekly suspension in autoinjector to exenatide 10 mcg twice daily, sitagliptin, and placebo (controlled treatment period only). Background therapies included diet and exercise, alone or in combination with metformin, a sulfonylurea, a thiazolidinedione or a combination of oral anti-diabetic agents.

Hypoglycaemia.

As would be expected, the incidence of hypoglycaemia was increased when exenatide was used in combination with a sulfonylurea (see Section 4.4 Special Warnings and Precautions for Use). To reduce the risk of hypoglycaemia associated with the use of a sulfonylurea, reduction in the dose of sulfonylurea may be considered (see Section 4.2 Dose and Method of Administration; Section 4.4 Special Warnings and Precautions for Use). Most episodes of hypoglycaemia were mild to moderate in intensity, and all resolved with oral administration of carbohydrate.

Bydureon kit and pen.

Exenatide was associated with a significantly lower incidence of episodes of hypoglycaemia than insulin glargine in patients receiving metformin therapy alone (3% versus 19%) and in patients receiving metformin plus sulfonylurea therapy (20% versus 42%).
Exenatide once weekly in combination with basal insulin showed no clinically significant differences in the incidence of hypoglycaemic episodes compared to insulin. There were no episodes of major hypoglycaemia in the exenatide once weekly with insulin group.
Table 3 summarises the occurrence of treatment emergent hypoglycaemia by sulfonylurea use in clinical trials of 2 mg exenatide once weekly.

Bydureon BCise autoinjector.

There were no events of major hypoglycaemia with exenatide once weekly suspension in autoinjector. The overall incidence of minor hypoglycaemia was 6.3%. This incidence was increased when it was used in combination with a sulfonylurea (26.1%) compared to no sulfonylurea (0.9%) (see Section 4.4 Special Warnings and Precautions for Use).

Nausea.

Bydureon kit and pen.

Nausea has been described in studies of GLP-1 receptor agonists. In clinical trials of 2 mg exenatide once weekly, the most frequently reported adverse reaction was nausea. In patients treated with 2 mg exenatide once weekly, generally 20% reported at least one episode of nausea compared to 34% of 10 microgram 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 from clinical trials due to adverse events was approximately 5% for exenatide once weekly treated patients and 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 approximately 1% for exenatide once weekly treated patients and exenatide twice daily treated patients.

Bydureon BCise autoinjector.

During the controlled period of the clinical trial comparing exenatide once weekly suspension in autoinjector with exenatide twice daily, nausea was reported in 9.6% and 20.5% of patients in each respective group. Overall, 9.3% of patients treated with exenatide once weekly in autoinjector reported nausea during the controlled period of both clinical trials. Most episodes of nausea were mild to moderate, associated with the initiation of treatment and decreased over time.

Immunogenicity.

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

Bydureon kit and pen.

In the clinical trials of exenatide once weekly, approximately 45% of patients had low titre antibodies to exenatide at study endpoint. Consistent with exenatide twice daily clinical trial results, the level of glycaemic control (HbA1c) was generally comparable to that observed in those without antibody titres (51% of patients). Approximately 5% of patients had higher titre antibodies at study endpoint. In one-third of these (2% overall), the glycaemic response to exenatide once weekly was attenuated; the remaining 4% had a glycaemic response comparable to that of patients without antibodies.
Overall the percentage of antibody positive patients was consistent across clinical trials. 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 exenatide once weekly treated patients, the incidence of potentially immunogenic injection site reactions (most commonly pruritus with or without erythema) during the 30 week and 26 week studies was approximately 10%. 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).

Bydureon BCise autoinjector.

Anti-exenatide antibodies were measured at prespecified intervals in 393 exenatide once weekly suspension-treated patients in the two comparator-controlled studies for exenatide once weekly suspension in autoinjector. At the study endpoint, approximately 43.4% of patients had low titre antibodies to exenatide and approximately 13.9% of patients had high titre antibodies.
Consistent with exenatide twice daily and exenatide once weekly clinical trial results, change in HbA1c from baseline in exenatide once weekly suspension in autoinjector treated patients with low titre antibodies at the last visit (-1.1 to -1.5%) was generally comparable to that observed in antibody-negative patients at the last visit (-1.1 to -1.4%). While patients with high titre antibodies at the last visit had an attenuated HbA1c response, HbA1c reductions in these patients were clinically relevant (-0.6 to -0.7%).
Amongst exenatide once weekly suspension in autoinjector treated patients evaluable for antibodies (N=393), the incidence of potentially immunogenic injection site reactions (most commonly injection site nodule) during the 28-week studies was approximately 19.6%. These reactions were less commonly observed in antibody-negative patients (15.7%) and patients with low titre antibodies (16.3%) compared with those with high titre antibodies (27.2%).

Injection site reactions.

Injection site reactions were observed more frequently (approximately 2-fold) in exenatide treated patients versus comparator treated patients. These injection site reactions were generally mild and usually did not lead to withdrawal from studies.
Injection site reactions were higher in exenatide once weekly treated patients (16%) compared to exenatide twice daily treated patients (2-7%). The reactions were pruritus (8%), erythema (4%), induration (4%) and nodule (3%). There was also asymptomatic nodule formation (up to 77%). Approximately 73% of the first incidence of treatment emergent injection site reactions resolved within 60 days.
Small subcutaneous injection site nodules were observed very frequently in clinical trials, consistent with the known properties of poly (D,L-lactide coglycolide) polymer microsphere formulations. Most individual nodules were asymptomatic, did not interfere with study participation and resolved over 4 to 8 weeks.

Drug-induced thrombocytopenia.

Drug-induced thrombocytopenia (DITP) with exenatide-dependent antiplatelet antibodies has been reported in the postmarketing setting. DITP is an immune mediated reaction that is caused by drug-dependent platelet-reactive antibodies. These antibodies cause destruction of platelets in the presence of the sensitising drug.

Spontaneous data.

General.

Common (≥ 1% and < 10%): injection site reactions.

Gastrointestinal disorders.

Uncommon (≥ 0.1% and < 1%): abdominal distension, abdominal pain, eructation, constipation, flatulence, nausea, vomiting, diarrhoea. Rare (≥ 0.01% and < 0.1%): acute pancreatitis. Very rare (< 0.01%): cases of ileus, ischaemic colitis and gut ischaemia have been reported.

Nervous system disorders.

Uncommon (≥ 0.1% and < 1%): dysgeusia. Rare (≥ 0.01% and < 0.1%): somnolence.

Investigations.

Rare (≥ 0.01% and < 0.1%): INR increased with concomitant warfarin use, some reports associated with bleeding (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Immune system disorder.

Very rare (< 0.01%): anaphylactic reaction.

Skin and subcutaneous disorders.

Rare (≥ 0.01% and < 0.1%): angioedema, generalized pruritus and/or urticaria, macular or papular rash, alopecia. Very rare (< 0.01%): injection site abscess, infection, necrosis.

Metabolism and nutritional disorders.

Rare (≥ 0.01% and < 0.1%): dehydration, generally associated with nausea, vomiting, and/or diarrhoea, weight decreased (see Section 4.4 Special Warnings and Precautions for Use, Weight loss).

Renal and urinary disorders.

Rare (> 0.01% and < 0.1%): acute renal failure, chronic renal failure, renal impairment, increased serum creatinine (see Section 4.4 Special Warnings and Precautions for Use).

Blood and lymphatic system disorders.

Frequency not known: drug-induced thrombocytopenia.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

The recommended Bydureon dose is 2 mg exenatide once weekly. Titration is not required. Bydureon is for single-use in one patient only. Discard any residue.
Bydureon can be administered at any time of day, with or without meals.
After suspension, use Bydureon only if the mixture is white to off white and cloudy. Each dose should be administered in the abdomen as a subcutaneous injection immediately after suspension of the powder in the diluent. Bydureon must not be administered intravenously or intramuscularly.
When used in combination with insulin, Bydureon and insulin must be administered as two separate injections. It is acceptable to inject Bydureon and insulin in the same region of the body, but the injections should not be adjacent to each other.
Bydureon kit and pen must be injected immediately after suspension of the powder in the diluent. Bydureon BCise autoinjector must be injected immediately after mixing the suspension.

Changing weekly dosing schedule.

The day of weekly administration can be changed if necessary as long as the last dose was administered 3 or more days before.

Missed dose.

If a dose is missed, it should be administered as soon as noticed, provided the next regularly scheduled dose is due at least 3 days later. Thereafter, patients can resume their usual dosing schedule of once every 7 days (weekly).
If a dose is missed and the next regularly scheduled dose is due 1 or 2 days later, the patient should not administer the missed dose and instead resume Bydureon with the next regularly scheduled dose.

Use in combination therapy.

Bydureon is recommended for use in patients with type 2 diabetes mellitus who are already receiving metformin and/or a sulfonylurea.
When Bydureon is added to existing metformin therapy, the current dose of metformin can be continued as no increased risk of hypoglycaemia is anticipated, compared to metformin alone.
When Bydureon is added to sulfonylurea therapy, a reduction in the dose of sulfonylurea should be considered to reduce the risk of hypoglycaemia (see Section 4.4 Special Warnings and Precautions for Use).
When Bydureon is added to dapagliflozin, no dose adjustment is required.
When Bydureon was added to a basal insulin, no initial dose adjustment of insulin was required if the fasting blood glucose level was in the target range.
Bydureon can be used in addition to metformin and basal insulin. In a clinical trial with basal insulin, patients ceased therapy with a sulfonylurea - there are no data on the risk/benefit of continuing sulfonylurea therapy.

Switching from Byetta to Bydureon.

Patients switching from Byetta (10 microgram exenatide twice daily) to Bydureon (2 mg exenatide once weekly) may experience transient elevations in blood glucose concentrations, which generally improve within the first two weeks after initiation of therapy.

Switching between Bydureon kit or pen to Bydureon BCise autoinjector.

Patients switching between Bydureon kit or pen and Bydureon BCise autoinjector may do so, with minimal expected effect on blood glucose concentrations.

Monitoring.

The use of Bydureon does not require additional self-monitoring. However, when used in combination with a sulfonylurea, or insulin, blood glucose self-monitoring may be necessary to monitor for hypoglycaemia and to titrate the doses of insulin or sulfonylurea.

Discontinuation.

Following discontinuation, consideration should be given to the prolonged release of exenatide (see Section 5.2 Pharmacokinetic Properties).

Specific patient groups.

Elderly.

Bydureon can be given to adults of all ages including the elderly (> 65 years of age) (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).

Patients with renal impairment.

Bydureon can be given to patients with mild or moderate renal impairment (creatinine clearance 30-80 mL/min) (see Section 5.2 Pharmacokinetic Properties).
Bydureon is not recommended for use in patients with endstage renal disease or severe renal impairment (creatinine clearance < 30 mL/min) (see Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

Bydureon can be given to patients with hepatic impairment (see Section 5.2 Pharmacokinetic Properties).

Children and adolescents.

The safety and efficacy of exenatide have not yet been established in children under 18 years of age (see Section 5.2 Pharmacokinetic Properties).

Instructions for use and handling.

Bydureon is for use by one person only.
The instructions for the user containing the complete preparation and administration instructions must be followed carefully.
The diluent should be visually inspected prior to use. Use the diluent only if it is clear and free of particulate matter. After suspension, use Bydureon only if the mixture is white to off white and cloudy.
Bydureon should be used only with the supplied custom needles.
Bydureon kit and pen must be injected immediately after suspension of the powder in the diluent. Bydureon BCise autoinjector must be injected immediately after mixing the suspension.
Bydureon that has been frozen must not be used.
Bydureon should not be used past the expiration date.
The patient should be instructed to discard the syringe, pen or autoinjector with the needle still attached after each injection in an appropriate needle bin and return, along with any unused medicinal product or waste material to pharmacists or diabetes nurse educators for disposal. The patient does not need to put the cover back on the needle or to save any part of the single use kit, single use pen or single use autoinjector.

4.7 Effects on Ability to Drive and Use Machines

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

4.9 Overdose

Effects of overdoses with 10 microgram exenatide twice daily in 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.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Bydureon BCise autoinjector.

Powder. Polyglactin, sucrose.
Vehicle. Medium chain triglycerides.

Bydureon kit and pen.

Powder. Polyglactin, sucrose.
Diluent. Carmellose sodium, sodium chloride, polysorbate 20, monobasic sodium phosphate monohydrate, dibasic sodium phosphate (as heptahydrate), water for injections.
Sodium hydroxide may be added during manufacture of the Bydureon pre-filled pen for pH adjustment.

6.2 Incompatibilities

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

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

During the shelf life, Bydureon should be stored at 2°C to 8°C. However, Bydureon may be kept for up to 4 weeks below 30°C during the shelf life. Refrigerate. Do not freeze. Store flat and in the original pack to protect from light.

6.5 Nature and Contents of Container

Bydureon BCise autoinjector.

Bydureon BCise (exenatide suspension for injection autoinjector) for weekly subcutaneous administration is supplied in cartons containing 4 single dose autoinjectors or 1 single dose autoinjector.
The suspension is packaged in a 2 mL Type 1 glass cartridge, sealed at one end with a rubber seal/cap combination, and at the other end with a rubber plunger. The finished drug product is comprised of the suspension filled cartridge assembled into the autoinjector device. The autoinjector contains an integrated needle.

Bydureon pen.

Bydureon (exenatide powder and solvent for injection pre-filled pen) for weekly subcutaneous administration is supplied in cartons containing either 4 single dose dual-chamber pens or 1 single dose dual-chamber pen.
Each pre-filled pen contains exenatide powder and solvent for suspension for injection. The powder and solvent are packaged in a Type 1 glass cartridge sealed at one end with a rubber stopper and an aluminium seal, and at the other end with a rubber piston. The two chambers are separated by a second rubber piston.
There is one needle supplied per pen. Each carton also contains one spare needle. Use only the supplied needles with the pen.

Bydureon kit.

Bydureon (exenatide powder for injection vial with diluent syringe) for weekly subcutaneous administration is supplied in cartons containing 4 single dose kits.
Exenatide powder for injection is packaged in a 3 mL Type I glass vial sealed with a rubber stopper and an aluminium seal with a plastic flip-off cap.
The diluent (solvent) is packaged in a 1.5 mL Type 1 glass syringe sealed with a rubber tip cap and a rubber plunger.
Each single-dose kit contains one vial of exenatide powder for suspension for injection, one pre-filled syringe of diluent for injection, one vial connector, and two needles (one spare).

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes