Consumer medicine information

Byetta

Exenatide

BRAND INFORMATION

Brand name

Byetta Solution for injection

Active ingredient

Exenatide

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Byetta.

What is in this leaflet

This leaflet answers some common questions about BYETTA.

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 BYETTA 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 BYETTA is used for

BYETTA is an injectable medicine used to improve blood sugar control in adults with type 2 diabetes mellitus. It is used with metformin or a sulfonylurea. It may also be used with a combination of both metformin and a sulfonylurea. Your medicine can also be used in combination with a long acting insulin and metformin.

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

BYETTA 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 BYETTA

When you must not use it

Do not use BYETTA if:

  • you have type 1 diabetes or diabetic ketoacidosis (often caused by very high blood glucose levels)
  • you are allergic to exenatide or meta-Cresol 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 the BYETTA pen 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.

Do not use the BYETTA pen if you see solid particles or if the solution is cloudy or coloured.

Do not use the BYETTA pen if the pen has been in use for 30 days, even if there is medicine left in the pen.

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

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.

BYETTA 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 BYETTA or may affect how it works.

These include:

  • medicines that need to pass through the stomach quickly for absorption. BYETTA slows stomach emptying and can affect these medicines
  • other medicines used to stimulate insulin secretion to control your blood sugar levels
  • bisphosphonates, a type of medicine used to treat osteoporosis
  • tetracyclines
  • statins, a type of medicine used to lower cholesterol
  • oral contraceptives or oral antibiotics. These should be taken at least 1 hour before taking BYETTA
  • warfarin, a medicine used to prevent blood clots. Taking BYETTA while you are taking warfarin may cause you to bleed more easily

You can still take the following medicines while you are taking BYETTA. However, you must take the following medicines at least 1 hour before or at least 4 hours after taking BYETTA.

  • proton pump inhibitors, a type of medicine to treat stomach ulcers or acid in your stomach

Using BYETTA with the following medicines may affect your kidneys.

  • 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

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

How to use BYETTA

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.

Ask your doctor or healthcare professional which needle length and gauge is best for you.

Needles are not included with the pen.

How to use it

BYETTA is given by injection under the skin (subcutaneous) into the thigh, abdomen or upper arms.

BYETTA comes in a pre-filled pen with fixed dosing. Your health care professional should teach you how to use the BYETTA pen.

Read the User Manual for information on how to use the pen before beginning therapy.

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

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

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

If you are also taking insulin, you must inject your insulin at a separate site from your BYETTA injection.

How much to use

BYETTA is available as a 5 microgram dose and as a 10 microgram dose. It is usual for your doctor to start your BYETTA therapy with the lower dose.

Use BYETTA exactly as prescribed by your doctor.

Your doctor will tell you how much of this medicine you need to use each day. Any change in dose should be made cautiously and only under medical supervision.

When to use it

Inject BYETTA twice a day, within 60 minutes (1 hour) before your morning and evening meals (or two main meals of the day, approximately 6 hours or more apart).

Do not use BYETTA after your meal.

How long to use it

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

If you forget to use it

If you miss a dose of BYETTA, skip that dose and inject your next dose at the next prescribed time.

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

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 BYETTA, 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 BYETTA

Things you must do

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

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

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

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 BYETTA 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.

You may need to inject your BYETTA and eat your meals at different times because of time differences in and between countries.

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 BYETTA in combination with a sulfonylurea, 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 BYETTA.

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

Tell your doctor if you experience hypoglycaemia.

Tell your doctor if you notice any of the following:

  • nausea
  • vomiting
  • diarrhoea
  • 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)
  • indigestion (dyspepsia)
  • excessive sweating (hyperhidrosis)

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

When using BYETTA some patients have lost more than 1.5 kg of weight per week. Rapid weight loss of this rate may be harmful. Tell your doctor if you experience rapid weight loss.

Not all patients will lose weight. BYETTA may reduce your appetite. Nausea and vomiting were very commonly reported in patients using BYETTA. 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
  • bleeding more easily than normal, if you are taking warfarin

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

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

  • persistent, 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 BYETTA.

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 BYETTA

Storage

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

You may keep your BYETTA pen below 25°C for up to 30 days while you are using the pen. Do not put your BYETTA pen near heat or in the sun.

Keep this medicine where children cannot reach it.

Remove the needle immediately after you have given your injection.

Use a new needle for each injection.

Do not store your pen with the needle attached.

If you do this, it may allow solution to leak from the pen and air bubbles to form in the cartridge.

Each BYETTA pen can be used for up to 30 days after the first injection.

Discard the pen after 30 days, even if it contains some unused solution.

Ask your pharmacist how to discard the pen.

The BYETTA pen is for use in a single patient only.

Disposal

Dispose of your needles and pen safely into a yellow plastic sharps container or similar puncture proof container composed of hard plastic or glass.

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

BYETTA is a clear colourless liquid. It is supplied in a 5 microgram or 10 microgram pre-filled delivery device (pen). Each pen contains dosing for 30 treatment days.

BYETTA is available in packs of 1 pen.

Ingredients

BYETTA contains:

250 microgram/mL of exenatide as the active ingredient.

It also contains:

  • acetic acid - glacial
  • meta-Cresol
  • mannitol
  • sodium acetate
  • water for injection

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 Number

BYETTA 5 mcg (exenatide 5 microgram/20 microlitre)
AUST R 123609

BYETTA 10 mcg (exenatide 10 microgram/40 microlitre)
AUST R 123610

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 BYETTA.

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 March 2017.

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

Doc ID-002465178 V3.0

BRAND INFORMATION

Brand name

Byetta Solution for injection

Active ingredient

Exenatide

Schedule

S4

 

1 Name of Medicine

Exenatide.

6.7 Physicochemical Properties

Chemical structure.

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.

141732-76-5.

2 Qualitative and Quantitative Composition

Byetta 5 micrograms solution for injection.

Byetta 5 microgram pre-filled pen contains 60 doses of sterile, preserved isotonic solution (approximately 1.2 mL). Each dose contains 5 microgram exenatide in 20 microlitres (0.25 mg synthetic exenatide per mL).

Byetta 10 micrograms solution for injection.

Byetta 10 microgram pre-filled pen contains 60 doses of sterile, preserved isotonic solution (approximately 2.4 mL). Each dose contains 10 microgram exenatide in 40 microlitres (0.25 mg synthetic exenatide per mL).
Each millilitre of Byetta contains 250 microgram of synthetic exenatide.
For a full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Solution for injection. Byetta is a clear colourless solution.

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 (see Section 4.4 Special Warnings and Precautions for Use).
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.
In the insulin-comparator controlled studies, exenatide was associated with a significant reduction in postprandial blood glucose excursions compared with insulin glargine (p < 0.0001) and biphasic insulin aspart (p < 0.0001) (see Figure 1).

Beta-cell function.

Exenatide stimulates insulin release - clinical trial data 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. Most clinical benefit in glycaemic control is seen within 12 weeks of commencement. An increase in pancreatic islet cell mass has not been consistently demonstrated in animal models.

Clinical trials.

Use in combination with metformin and/or a sulfonylurea.

Efficacy of exenatide in treatment of type 2 diabetes has been established in 5 pivotal placebo- or active comparator-controlled clinical trials, involving 2,496 patients, 1,498 of whom received exenatide. The primary objectives of these clinical trials were to evaluate glycaemic control, primarily as assessed by HbA1c. The secondary objectives included examining the effects of exenatide on fasting and postprandial plasma glucose concentrations, bodyweight and fasting concentrations of circulating insulin, proinsulin and lipids.
Exenatide treatment results in improvement in glycaemic control as measured by HbA1c over the dosing period with most benefit obtained by about the twelfth week of treatment (see Figure 2 and Table 5). In the three placebo controlled clinical trials, the mean (± SD) change from baseline in fasting plasma glucose was -0.4 ± 2.8 mmol/L and -0.6 ± 2.7 mmol/L with exenatide 5 and 10 microgram BID, respectively, compared to an increase of 0.7 ± 2.9 mmol/L in the placebo arm at week 30. In addition, sustained reductions in postprandial glucose concentrations were observed during meal challenge tests at weeks 4 and 30.
In insulin comparator trials, exenatide reduced postprandial glucose excursions more than insulin glargine or biphasic insulin aspart, while insulin glargine reduced fasting glucose concentrations (p < 0.0001) more than exenatide.
Patients treated with exenatide may exhibit progressive weight reduction. No specific studies on appetite or weight loss have been conducted. The precise mechanism of weight loss is unknown. The administration of exenatide is also associated with nausea and vomiting (see Section 4.8 Adverse Effects (Undesirable Effects)).
In three separate clinical trials when exenatide was used in combination with metformin, sulfonylurea, or a combination of both, significant improvements in glucose control were observed compared to placebo (see Table 5).
When exenatide was used in combination with metformin and sulfonylurea similar improvements in glucose control were observed in two clinical trials, one comparing with insulin glargine and the other comparing with biphasic insulin aspart (see Table 6).
The glucose lowering effect of exenatide can be seen immediately following the first injection. The average reduction in HbA1c (approximately 1%) is generally observable by 12 weeks after initiation of treatment. Figures 2, 3 and 4 show the mean HbA1c over time in patients with type 2 diabetes using exenatide or placebo together with metformin, sulfonylurea, or a combination of both. A sustained reduction of HbA1c has been shown through at least 52 weeks of therapy in a controlled study and 82 weeks in uncontrolled studies. In the 30 week placebo-controlled studies, 33.6% of patients using exenatide 10 microgram BID together with metformin, sulfonylurea or a combination of both achieved HbA1c ≤ 7.0%. The ≤ 7.0% HbA1c goal was achieved by 46.4% of exenatide-treated versus 48% of insulin glargine-treated subjects in the 26 week study and by 31.7% of exenatide-treated and 24.1% of biphasic insulin aspart-treated subjects in the 52 weeks study (see Table 7).

Bodyweight.

Exenatide significantly reduced patient body weight in Phase 3 studies (placebo and insulin comparator controlled). Patients who continued in an uncontrolled open label extension to the placebo controlled studies continued to lose weight through 82 weeks of treatment. The long-term outcomes (morbidity, mortality, or the clinical benefits) associated with these effects have not been studied.
Weight loss of 2.3 kg (2.6%, p < 0.0001) was achieved in a 26-week insulin glargine comparator study and a loss of 2.5 kg (2.7%) in a 52-week biphasic insulin aspart comparator study whereas treatment with insulin was associated with weight gain. See Figures 5 and 6.
The total estimated treatment difference (exenatide minus comparator) was -4.1 kg in the 26-week study and -5.4 kg in the 52-week study.
The results of three 30 weeks randomised triple-blind, placebo controlled trials showed significantly greater reductions from baseline in bodyweight with exenatide 5 or 10 microgram BID daily than with placebo in patients receiving exenatide and metformin alone (-1.3 kg and -2.6 kg versus -0.2 kg) or exenatide and metformin plus a sulfonylurea (-1.6 kg and -1.6 kg vs -0.9 kg). In patients receiving exenatide and sulfonylurea only, only patients on exenatide 10 microgram BID achieved a significantly greater reduction in body weight than placebo (-1.6 kg versus -0.8 kg) (see Figure 7).
In patients receiving exenatide and metformin alone, weight reduction was statistically significant for patients with a baseline BMI < 30 kg/m2 and ≥ 30 kg/m2 for exenatide 10 microgram BID but not for the exenatide 5 microgram BID compared with placebo. For patients receiving exenatide and sulfonylurea alone, the change in body weight was statistically significant in patients with a baseline BMI < 30 kg/m2 for exenatide 10 microgram BID compared with placebo but not for exenatide 5 microgram BID or patients with a BMI ≥ 30 kg/m2. For the exenatide with metformin and sulfonylurea patients, a statistically significant reduction in bodyweight was observed for each exenatide treatment (5 microgram, BID and 10 microgram, BID) compared with placebo with baseline BMI ≥ 30 kg/m2 but not for subjects with baseline BMI < 30 kg/m2.
The observed weight loss was not necessarily secondary to nausea and other gastrointestinal side effects, as weight loss was also observed in those subjects who did not experience these adverse events.

Effect on lipids.

Exenatide has shown no adverse effects on lipid parameters. A trend for a decrease in triglycerides has been observed. An improvement in high density lipoprotein and an improvement in triglyceride levels have been correlated with greater weight loss at 82 weeks in exenatide treated patients. The long-term outcomes (morbidity, mortality, or the clinical benefits) associated with these effects have not been studied.

Use in combination with a basal insulin.

In a 30 week study, either exenatide (5 microgram BID for 4 weeks, followed by 10 microgram BID) or a placebo was added to insulin glargine (with or without metformin, pioglitazone or both). During the study both treatment arms titrated insulin glargine using an algorithm reflecting current clinical practice to a target fasting plasma glucose of approximately 5.6 mmol/L. The mean age of subjects was 59 years and the mean duration of diabetes was 12.3 years.
At the end of the study, exenatide (n = 137) demonstrated a statistically significant reduction in HbA1c, the primary objective of the study. In relation to the secondary objective, body weight also was significantly reduced compared to placebo in patients receiving titrated insulin glargine. Based on additional secondary objectives, the proportion of patients achieving HbA1c < 7% and ≤ 6.5% was greater in patients treated with exenatide compared to placebo. Reductions in insulin units/day, fasting serum glucose and postprandial glucose excursions after the morning and evening meal were greater with exenatide compared to placebo (see Table 8).
When exenatide was added to existing basal insulin therapy (insulin glargine), the dose of basal insulin was decreased by 20% in patients with an HbA1c ≤ 8.0%, per protocol design in order to minimise the risk of hypoglycaemia. Both treatment arms were titrated to achieve target fasting plasma glucose levels. There were no clinically significant differences in the incidence of hypoglycaemic episodes in the exenatide group compared to the placebo group (25% and 30% respectively). There were no episodes of major hypoglycaemia in the exenatide arm.

5.2 Pharmacokinetic Properties

Absorption.

Following subcutaneous administration to patients with type 2 diabetes, exenatide reaches median peak plasma concentrations in 2.1 h. Mean peak exenatide concentration (Cmax) was 211 picogram/mL and overall mean area under the curve (AUC0-inf) was 1036 picogram.h/mL following subcutaneous administration of a 10 microgram dose of exenatide. Exenatide exposure (AUC) increased proportionally over the therapeutic dose range of 5 microgram to 10 microgram. The Cmax values increased less than proportionally over the therapeutic dose range of 5 microgram to 10 microgram. Similar exposure is achieved with subcutaneous administration of exenatide in the abdomen, thigh, or arm. Following subcutaneous administration of a single 10 microgram dose of exenatide in the abdomen, thigh and arm, mean Cmax was 251 picogram/mL, 220 picogram/mL and 245 picogram/mL, respectively; mean AUC was 1200 picogram.h/mL, 1130 picogram.h/mL and 1080 picogram.h/mL, respectively.

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. In most individuals, exenatide concentrations are measurable for approximately 10 h postdose.

Special populations.

Patients with renal impairment.

In patients with mild to moderate renal impairment (creatinine clearance 30 to 80 mL/min), exenatide clearance was only mildly reduced compared to clearance in individuals with normal renal function. Clearance was significantly reduced to 0.9 L/h in patients with end-stage renal disease receiving dialysis compared with 9.1 L/h in healthy subjects (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, obesity.

Gender, race or obesity has no significant 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 patients with type 2 diabetes, administration of exenatide (10 microgram) 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.

In female rats given exenatide for 2 years, an increased incidence of benign thyroid C-cell adenomas was observed at the highest dose (250 microgram/kg/day), a dose that produced an exenatide plasma exposure 110 times the human clinical exposure at 20 microgram/day. There was no tumorigenic response in male rats or either sex of mice at exposures 80 (mouse) and 110 (rat) times the human exposure.

4 Clinical Particulars

4.1 Therapeutic Indications

Exenatide is indicated as adjunctive therapy to improve glycaemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea, or a combination of metformin and a basal insulin, but are not achieving adequate glycaemic control.

4.3 Contraindications

Exenatide is contraindicated in patients with known hypersensitivity to this product or any of its components, including metacresol (see Section 6.1 List of Excipients).
Exenatide should not be used in patients with end-stage 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 end-stage renal disease receiving dialysis, resulting in poor gastrointestinal tolerability.

4.4 Special Warnings and Precautions for Use

General.

Exenatide 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 exenatide is not recommended in patients with severe gastrointestinal disease including gastroparesis and dumping syndrome.
The concurrent use of exenatide with D-phenylalanine derivatives, meglitinides, alpha-glucosidase inhibitors, orlistat, opioids, and anticholinergics has not been studied. Exenatide in combination with a thiazolidinedione is not recommended as there is limited experience.
Exenatide is not a substitute for insulin in insulin-requiring patients. Exenatide should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. The substitution of exenatide for insulin in insulin-requiring patients has not been extensively studied. In a 16 week exploratory study, which evaluated the safety of substituting exenatide for insulin in 33 patients with type 2 diabetes using insulin in combination with oral antidiabetic agents, almost 40% of subjects were unable to maintain glycaemic control (experienced an increase of HbA1c ≥ 0.5%) while on exenatide.
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).
Exenatide should be used with caution and dose escalation from 5 microgram to 10 microgram should proceed conservatively in patients > 70 years. The clinical experience in patients > 75 years is very limited.

Hypoglycaemia.

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, patients on a sulfonylurea 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 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)).
Due to the glucose-dependent insulinotropic mechanism of action of exenatide, when used in combination with metformin alone, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin (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. For many events, reversibility has been observed with appropriate treatment (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 anti-diabetic treatments, including exenatide, for these patients. The change in risk of recurrent pancreatitis in patients with a past history of pancreatitis who receive exenatide 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 exenatide.
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 exenatide 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.

Use in renal impairment.

In patients with mild to moderate renal impairment (creatinine clearance > 30 to 80 mL/min), exenatide clearance was only mildly reduced compared to clearance in individuals with normal renal function. Patients with moderate renal impairment (creatinine clearance > 30 to 50 mL/min) have been noted to have an increase in the AUC of exenatide. As the risk of adverse events is dose-dependent, caution is recommended in this population (see Section 4.3 Contraindications).

Use in the elderly.

No dosage adjustments are necessary for use of exenatide in elderly patients. Subjects aged up to 75 years were enrolled in the 5 placebo- and active comparator-controlled pivotal clinical studies. A total of 333 subjects aged 65 years or older received exenatide in these studies. There were no apparent age-related differences in the change in HbA1c values from baseline to endpoint for subjects treated with exenatide during these studies.

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.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Exenatide stimulates insulin release. This should be considered when insulin secretagogues are used (for use with sulfonylurea, see Section 5.1 Pharmacodynamic Properties, Clinical trials).
Exenatide slows gastric emptying, as part of its mechanism of action. This has the potential for interaction with orally administered medicines. Exenatide should be used with caution in patients receiving oral medications that require rapid gastrointestinal absorption or medication associated with local gastrointestinal irritation such as bisphosphonates or tetracyclines. Gastro-resistant formulations containing substances sensitive to degradation in the stomach, such as proton pump inhibitors, should be taken at least 1 hour before or more than 4 hours after exenatide injection. For oral medications that are particularly dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those medicines at least 1 hour before exenatide injection. If such medicines are to be administered with food, patients should be advised to take them with a meal or snack when exenatide is not administered.

Paracetamol.

Paracetamol was used as a model medicinal product to evaluate the effect of exenatide on gastric emptying. When 1000 mg paracetamol was given with 10 microgram exenatide (0 h) and 1 h, 2 h and 4 h after exenatide injection, paracetamol AUCs were decreased by 21%, 23%, 24% and 14% respectively; Cmax was decreased by 37%, 56%, 54% and 41% respectively; Tmax was increased from 0.6 h in the control period to 0.9 h, 4.2 h, 3.3 h and 1.6 h respectively. Paracetamol AUC, Cmax and Tmax were not significantly changed when paracetamol was given 1 hour before exenatide injection. No adjustment to paracetamol dosing is required based on these study results.

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 exenatide (10 microgram BID) was administered concomitantly with a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In the 30-week placebo controlled clinical trials, concomitant use of exenatide and HMG-CoA reductase inhibitors was not associated with consistent changes in lipid profiles. Although no predetermined dose adjustment is required, one should be aware of possible changes in LDL-C or total cholesterol. Lipid profiles should be monitored regularly.

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 30 min after exenatide. 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).

Digoxin and lisinopril.

No clinically relevant interactions were observed with digoxin and lisinopril.

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 was unaffected in mice treated with exenatide at SC doses up to 760 microgram/kg/day, 500 times the clinical exposure at 20 microgram/day based on AUC.
(Category C)
Exenatide 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/ new born 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 3, 30 and 500 times (mouse) and 0.2, 5, 200, 1400 and 3500 times (rabbit) the clinical exposure at 20 microgram/day. 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 body weight 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 500 times the clinical exposure at 20 microgram/day. The no observable effect level for peri-neonatal effects was 68 microgram/kg/day, giving exposures 30 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). Exenatide 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)

Use with metformin and/or a sulfonylurea.

The safety of exenatide has been evaluated in over 2500 exenatide-treated subjects in the completed clinical pharmacology, efficacy and safety studies, comprising 1729 subject years. Overall, 87% of exenatide-treated subjects experienced at least one treatment emergent adverse event, compared with 72% of insulin- and 64% of placebo-treated subjects. Among exenatide-treated subjects, nausea was the most common event (52%), followed by hypoglycaemia (27%) and vomiting (19%).
The incidence of withdrawal due to adverse events was 8% for exenatide-treated patients and 2% for placebo-treated or insulin-treated patients in the long-term controlled trials (26 weeks or longer). The most common adverse events leading to withdrawal for exenatide-treated patients were nausea (3% of patients) and vomiting (1%). For placebo-treated or insulin-treated patients, < 1% withdrew due to nausea and 0% due to vomiting.
Exenatide-treated patients in the open-label extension studies at 82 weeks experienced similar types of adverse events to those observed in the long-term controlled trials of 26 weeks or more.
Table 1 lists the adverse reactions reported from Phase 3 placebo, insulin glargine and 30% soluble insulin aspart/ 70% insulin aspart protamine crystal (biphasic insulin aspart) - comparator controlled studies in which the patients received metformin, a sulfonylurea or a combination of both in addition to exenatide or comparator.
The table presents adverse reactions that occurred with an incidence ≥ 5% and more frequently among exenatide-treated patients than insulin- or placebo-treated patients. The table also includes adverse reactions that occurred with an incidence ≥ 1% and with a statistically significantly higher and/or ≥ 2 x incidence among exenatide-treated patients than insulin- or placebo-treated patients.
The reactions are listed in Table 1 as MedDRA preferred term by system organ class and absolute frequency.
In the three 30-week controlled trials of exenatide add-on to metformin and/or sulfonylurea, adverse events with an incidence ≥ 5% (excluding hypoglycaemia; see Table 2) that occurred more frequently in exenatide-treated patients compared with placebo-treated patients are summarized in Table 2.

Hypoglycaemia.

Use with a sulfonylurea, metformin or both.

In 30-week placebo-controlled studies in patients treated with exenatide in combination with a sulfonylurea, or exenatide in combination with a sulfonylurea and metformin, the incidence of hypoglycaemia was increased over that of placebo in combination with a sulfonylurea, or placebo in combination with a sulfonylurea and metformin (see Section 4.4 Special Warnings and Precautions for Use) and appeared to be dependent on the doses of both exenatide and the sulfonylurea. Most episodes of hypoglycaemia were mild to moderate in intensity, and all resolved with oral administration of carbohydrate (see Table 3). In contrast, 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.
In the long-term active comparator (26 weeks or greater) studies in which all patients also received both metformin and a sulfonylurea the incidence of hypoglycaemia was similar for exenatide and insulin treatment (either insulin glargine or biphasic insulin aspart). Exenatide patients reported fewer episodes of nocturnal hypoglycaemia than insulin patients in both insulin glargine-comparator study (p < 0.001) and the biphasic insulin aspart-comparator study (p = 0.0384).
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).

Use with insulin.

When exenatide was added to existing titrated basal insulin therapy (insulin glargine), the incidence and types of adverse events observed were similar to those seen in the controlled clinical trials with exenatide in combination with metformin and/or sulfonylurea (see Table 4).

Nausea.

The most frequently reported adverse reaction, mild to moderate nausea, occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea.

Immunogenicity.

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-exenatide antibodies following treatment with exenatide. In most patients who develop antibodies, antibody titres diminish over time and remain low through 82 weeks.
In the three long-term placebo controlled trials, 38% of patients had low titre anti-exenatide antibodies at 30 weeks. For this group, the level of glycaemic control (HbA1c) was generally comparable to that observed in those without antibody titres. An additional 6% of patients had higher titre antibodies at 30 weeks. In about half of this 6% (3% of the total patients given exenatide in the controlled studies), the glycaemic response to exenatide appeared diminished; the remainder had a glycaemic response consistent with that of patients without antibodies. Patients who developed anti-exenatide antibodies tend to have more injection site reactions (for example: redness of skin and itching), but otherwise had similar rates and types of adverse events as those with no anti-exenatide antibodies. In the insulin-comparator controlled trials comparable efficacy and adverse events were observed in exenatide treated patients with and without antibody titres. Examination of antibody-positive specimens from one long-term uncontrolled study revealed no significant cross-reactivity with related endogenous peptides (glucagon or GLP-1).

Injection site reactions.

Injection site reactions have been reported in approximately 5.7% of subjects receiving exenatide in long term (26 weeks or longer) controlled clinical trials. These reactions have usually been mild and usually did not result in discontinuation of exenatide.

Drug-induced thrombocytopenia.

Drug-induced thrombocytopenia (DITP) with exenatide-dependent anti-platelet antibodies has been reported in the post-marketing 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. 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.

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, Weight loss).

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 any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Exenatide therapy should be initiated at 5 microgram exenatide per dose administered twice daily (BID) for at least one month in order to improve tolerability. The dose of Byetta can then be increased to 10 microgram BID to further improve glycaemic control. Doses higher than 10 microgram BID are not recommended.
Exenatide can be administered at any time within the 60-minute period before the morning and evening meals (or before the two main meals of the day, approximately 6 hours or more apart). Exenatide should not be administered after a meal. If an injection is missed, the treatment should be continued with the next scheduled dose.
Each dose of Byetta should be administered as a subcutaneous injection in the thigh, abdomen, or upper arm. Exenatide is not recommended to be administered by intravenous or intramuscular injection. Exenatide and basal insulin must be administered as two separate injections.
Exenatide is recommended for use in patients with type 2 diabetes mellitus who are already receiving metformin, a sulfonylurea, or both, or a basal insulin with metformin. When Byetta is added to metformin therapy, the current dose of metformin can be continued as no increased risk of hypoglycaemia is anticipated, compared to metformin alone. When Byetta is added to sulfonylurea therapy, a reduction in the dose of sulfonylurea may be considered to reduce the risk of hypoglycaemia (see Section 4.4 Special Warnings and Precautions for Use). When exenatide is used in combination with insulin, the dose of insulin should be evaluated. In patients at increased risk of hypoglycaemia consider reducing the dose of insulin (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The concurrent use of exenatide with prandial insulin has not been studied and cannot be recommended. Exenatide treatment should be ceased prior to commencing a basal bolus regimen.

Specific patient groups.

Gender, age, race or obesity.

No dosage adjustment is necessary for gender, for age, for race or for obese patients (BMI > 30 kg/m2) (see Section 5.2 Pharmacokinetic Properties).

Patients with renal impairment.

No dosage adjustment is necessary in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min) (see Section 5.2 Pharmacokinetic Properties).
In patients with moderate renal impairment (creatinine clearance: 30 to 50 mL/min), dose escalation from 5 microgram to 10 microgram should proceed conservatively (see Section 4.4 Special Warnings and Precautions for Use; Section 5.2 Pharmacokinetic Properties).
Exenatide should not be used in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 mL/min) (see Section 4.3 Contraindications; Section 5.2 Pharmacokinetic Properties).

Patients with hepatic impairment.

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

Children and adolescents.

Exenatide has not been studied in children and adolescents below 18 years.

Instructions for use and handling.

Each Byetta pen is for use by one person only. Instructions on how to use the pen are provided in the user manual. The instructions for using the pen must be followed carefully.
Exenatide should not be used if particles appear or if the solution is cloudy and coloured.
Exenatide that has been frozen must not be used.
The patient should be advised to discard the needle after each injection. Used needles should be disposed of in appropriate needle bin and returned to pharmacists or given to diabetes nurse educators for disposal. The pen is stored without the needle attached. The cartridge must not be refilled.

4.7 Effects on Ability to Drive and Use Machines

When exenatide 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

In a clinical study of exenatide, three patients with type 2 diabetes each experienced a single overdose of 100 microgram SC (10 times the maximum recommended dose). One of the three patients experienced severe hypoglycemia requiring parenteral glucose administration. The three patients recovered without complication.
In a spontaneously reported case of overdose, a patient was administered the total contents of an exenatide pen (approximately 300 microgram) that had been transferred to a syringe. The patient subsequently experienced severe nausea and vomiting, which resolved within 24 hours. The patient did not experience hypoglycaemia or a decline in blood glucose.
Signs and symptoms of overdose may include severe nausea, severe vomiting, rapidly declining blood glucose concentrations, and hypoglycemia possibly requiring prolonged treatment. In the event of overdose, appropriate supportive treatment (possibly given parenterally) 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

The excipients in Byetta are metacresol, mannitol, glacial acetic acid, sodium acetate, and water for injections.

6.2 Incompatibilities

Exenatide must not be mixed with other medicines.

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

Store at 2°C to 8°C. Refrigerate. Do not freeze. Protect from light.
Once in use the Byetta pen should be kept below 25°C and away from direct heat and light. Shelf life for pen in use is 30 days. The pen should be discarded 30 days after use, even if some medicine remains in the pen.
The Byetta pen should not be stored with the needle attached.

6.5 Nature and Contents of Container

Byetta is supplied in a type 1 glass cartridge that has been assembled into a disposable pen-injector (pen). Pack size of 1 Byetta pen.

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