BYETTA 5mcg / dose injection for pre-filled pen medication leaflet

Byetta 5 micrograms solution for injection in pre-filled pen

Byetta 10 micrograms solution for injection in pre-filled pen

Each dose contains 5 micrograms (mcg) of exenatide in 20 microlitres (mcl), (0.25 mg exenatideper mL).

Each dose contains 10 micrograms (mcg) of exenatide in 40 microlitres (mcl), (0.25 mg exenatideper mL).

Byetta 5 mcg: Each dose contains 44 mcg metacresol.

Byetta 10 mcg: Each dose contains 88 mcg metacresol.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless solution.

Byetta is indicated for treatment of type 2 diabetes mellitus in combination with:

- metformin

- sulphonylureas

- thiazolidinediones

- metformin and a sulphonylurea

- metformin and a thiazolidinedionein adults who have not achieved adequate glycaemic control on maximally tolerated doses of theseoral therapies.

Byetta is also indicated as adjunctive therapy to basal insulin with or without metformin and/orpioglitazone in adults who have not achieved adequate glycaemic control with these medicinalproducts.

Immediate-release exenatide (Byetta) therapy should be initiated at 5 mcg exenatide per doseadministered twice daily (BID) for at least one month in order to improve tolerability. The dose ofexenatide can then be increased to 10 mcg BID to further improve glycaemic control. Doses higherthan 10 mcg BID are not recommended.

Immediate-release exenatide is available as either a 5 mcg or a 10 mcg exenatide per dose pre-filledpen.

Immediate-release exenatide can be administered at any time within the 60-minute period before themorning and evening meal (or two main meals of the day, approximately 6 hours or more apart).

Immediate-release exenatide should not be administered after a meal. If an injection is missed, thetreatment should be continued with the next scheduled dose.

Immediate-release exenatide is recommended for use in patients with type 2 diabetes mellitus who arealready receiving metformin, a sulphonylurea, pioglitazone and/or a basal insulin. Immediate-releaseexenatide use can be continued when a basal insulin is added to existing therapy. Whenimmediate-release exenatide is added to existing metformin and/or pioglitazone therapy, the currentdose of metformin and/or pioglitazone can be continued as no increased risk of hypoglycaemia isanticipated, compared to metformin or pioglitazone alone. When immediate-release exenatide is addedto sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce therisk of hypoglycaemia (see section 4.4.). When immediate-release exenatide is used in combinationwith basal insulin, the dose of basal insulin should be evaluated. In patients at increased risk ofhypoglycaemia reducing the dose of basal insulin should be considered (see section 4.8).

The dose of immediate-release exenatide does not need to be adjusted on a day-by-day basisdepending on self-monitored glycaemia. Blood glucose self-monitoring is necessary to adjust the doseof sulphonylurea or insulin, particularly when Byetta therapy is started and insulin is reduced. Astepwise approach to insulin dose reduction is recommended.

Immediate-release exenatide should be used with caution and dose escalation from 5 mcg to 10 mcgshould proceed conservatively in patients > 70 years. The clinical experience in patients > 75 years isvery limited.

No dosage adjustment is necessary in patients with mild renal impairment (creatinine clearance50-80 mL/min).

In patients with moderate renal impairment (creatinine clearance 30-50 mL/min), dose escalation from5 mcg to 10 mcg should proceed conservatively (see section 5.2).

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

No dosage adjustment is necessary in patients with hepatic impairment (see section 5.2).

The efficacy of exenatide in children and adolescents under 18 years of age was not demonstrated.

Currently available data are described in sections 5.1 and 5.2 but no recommendation on a posologycan be made.

Each dose should be administered as a subcutaneous injection in the thigh, abdomen, or upper arm.

Immediate-release exenatide and basal insulin must be administered as two separate injections.

For instructions for using the pen, see section 6.6 and the user manual included with the leaflet.

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

Exenatide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabeticketoacidosis.

Exenatide is not a substitute for insulin. Diabetic ketoacidosis has been reported in insulin-dependentpatients after rapid discontinuation or dose reduction of insulin (see section 4.2)

Immediate-release exenatide must not be administered by intravenous or intramuscular injection.

In patients with end-stage renal disease receiving dialysis, single doses of immediate-releaseexenatide 5 mcg increased frequency and severity of gastrointestinal adverse reactions. Exenatide isnot recommended for use in patients with end-stage renal disease or severe renal impairment(creatinine clearance < 30 mL/min). The clinical experience in patients with moderate renalimpairment is very limited (see section 4.2).

There have been uncommon, spontaneously reported events of altered renal function, includingincreased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure,sometimes requiring hemodialysis. Some of these events occurred in patients experiencing events thatmay affect hydration, including nausea, vomiting, and/or diarrhoea and/or receiving medicinalproducts known to affect renal function/hydration status. Concomitant medicinal products includedangiotensin converting enzymes inhibitors, angiotensin-II antagonists, nonsteroidal anti-inflammatorymedicinal products and diuretics. Reversibility of altered renal function has been observed withsupportive treatment and discontinuation of potentially causative medicinal products, includingexenatide.

Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. Therehave been spontaneously reported events of acute pancreatitis with exenatide. Resolution ofpancreatitis has been observed with supportive treatment but very rare cases of necrotising orhemorrhagic pancreatitis and/or death have been reported. Patients should be informed of thecharacteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis issuspected, exenatide should be discontinued; if acute pancreatitis is confirmed, exenatide should notbe restarted. Caution should be exercised in patients with a history of pancreatitis.

Severe gastrointestinal disease

Exenatide has not been studied in patients with severe gastrointestinal disease, including gastroparesis.

Its use is commonly associated with gastrointestinal adverse reactions, including nausea, vomiting,and diarrhoea. Therefore, the use of exenatide is not recommended in patients with severegastrointestinal disease.

When immediate-release exenatide was used in combination with a sulphonylurea, the incidence ofhypoglycaemia was increased over that of placebo in combination with a sulphonylurea. In the clinicalstudies patients on a sulphonylurea combination, with mild renal impairment had an increasedincidence of hypoglycaemia compared to patients with normal renal function. To reduce the risk ofhypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylureashould be considered.

Rapid weight loss

Weight loss greater than 1.5 kg per week has been observed in approximately 5% of clinical trialpatients treated with exenatide. Weight loss of this rate may have harmful consequences. Patients withrapid weight loss should be monitored for signs and symptoms of cholelithiasis.

The effect of immediate-release exenatide to slow gastric emptying may reduce the extent and rate ofabsorption of orally administered medicinal products. Immediate-release exenatide should be usedwith caution in patients receiving oral medicinal products that require rapid gastrointestinal absorptionand medicinal products with a narrow therapeutic ratio. Specific recommendations regarding intake ofsuch medicinal products in relation to immediate-release exenatide is given in section 4.5.

The concurrent use of immediate-release exenatide with D-phenylalanine derivatives (meglitinides),alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists hasnot been studied and cannot be recommended.

This medicinal product contains metacresol, which may cause allergic reactions.

This medicinal product contains less than 1 mmol sodium per dose, i.e. essentially “sodium-free”.

The effect of immediate-release exenatide to slow gastric emptying may reduce the extent and rate ofabsorption of orally administered medicinal products. Patients receiving medicinal products of either anarrow therapeutic ratio or medicinal products that require careful clinical monitoring should befollowed closely. These medicinal products should be taken in a standardised way in relation toimmediate-release exenatide injection. If such medicinal products are to be administered with food,patients should be advised to, if possible, take them with a meal when immediate-release exenatide isnot administered.

For oral medicinal products that are particularly dependent on threshold concentrations for efficacy,such as antibiotics, patients should be advised to take those medicinal products at least 1 hour beforeimmediate-release exenatide injection.

Gastroresistant formulations containing substances sensitive for degradation in the stomach, such asproton pump inhibitors, should be taken at least 1 hour before or more than 4 hours afterimmediate-release exenatide injection.

Digoxin, lisinopril and warfarin

A delay in tmax of about 2 h was observed when digoxin, lisinopril or warfarin was administered30 min after exenatide. No clinically relevant effects on Cmax or AUC were observed. However, sincemarket introduction, increased INR (International Normalized Ratio) has been reported spontaneouslyduring concomitant use of warfarin and exenatide. INR should be closely monitored during initiationand dose increase of immediate-release exenatide therapy in patients on warfarin and/or cumarolderivatives (see section 4.8).

Metformin or sulphonylureas

Immediate-release exenatide is not expected to have any clinically relevant effects on thepharmacokinetics of metformin or sulphonylureas. Hence, no restriction in timing of intake of thesemedicinal products in relation to immediate-release exenatide injection are needed.

Paracetamol was used as a model medicinal product to evaluate the effect of exenatide on gastricemptying. When 1000 mg paracetamol was given with 10 mcg immediate-release exenatide (0 h) and1 h, 2 h and 4 h after immediate-release exenatide injection, paracetamol AUCs were decreased by21%, 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 hourbefore immediate-release exenatide injection. No adjustment to paracetamol dosing is required basedon these study results.

Hydroxy Methyl Glutaryl Coenzyme A (HMG CoA) reductase inhibitors

Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and tmax wasdelayed about 4 h when immediate-release exenatide (10 mcg BID) was administered concomitantlywith a single dose of lovastatin (40 mg) compared with lovastatin administered alone. In the 30-weekplacebo-controlled clinical trials, concomitant use of immediate-release exenatide and HMG CoAreductase inhibitors was not associated with consistent changes in lipid profiles (see section 5.1).

Changes in LDL-C or total cholesterol are possible, however, no predetermined dose adjustment isrequired. Lipid profiles should be monitored regularly.

Ethinyl estradiol and levonorgestrel

Administration of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcglevonorgestrel) one hour before immediate-release exenatide (10 mcg BID) did not alter the AUC,

Cmax or Cmin of either ethinyl estradiol or levonorgestrel. Administration of the oral contraceptive30 minutes after immediate-release exenatide 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 hdue to delayed gastric emptying. The reduction in Cmax is of limited clinical relevance and noadjustment of dosing of oral contraceptives is required.

Interaction studies have only been performed in adults.

If a patient wishes to become pregnant, or pregnancy occurs, treatment with exenatide should bediscontinued.

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

It is unknown whether exenatide is excreted in human milk. Exenatide should not be used ifbreast-feeding.

No fertility studies in humans have been conducted.

Exenatide has minor influence on the ability to drive and use machines. When exenatide is used incombination with a sulphonylurea or a basal insulin, patients should be advised to take precautions toavoid hypoglycaemia while driving and using machines.

The most frequent adverse reactions were mainly gastrointestinal related (nausea, vomiting anddiarrhoea). The most frequently reported single adverse reaction was nausea which was associatedwith the initiation of treatment and decreased over time. Patients may experience hypoglycaemia whenimmediate-release exenatide is used with a sulphonylurea. Most adverse reactions associated withimmediate-release exenatide were mild to moderate in intensity.

Since immediate-release exenatide has been marketed, acute pancreatitis has been reported with afrequency not known and acute renal failure has been reported uncommonly (see section 4.4).

Table 1 lists adverse reactions reported of immediate-release exenatide from clinical trials andspontaneous reports (not observed in clinical trials, frequency not known).

In clinical trials, background therapies included metformin, a sulphonylurea, a thiazolidinedione, or acombination of oral glucose-lowering medicinal products.

The reactions are listed below as MedDRA preferred term by system organ class and absolutefrequency. Frequencies are defined as: very common (≥ 1/10), common (≥ 1/100 to  1/10),uncommon ( 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and notknown (cannot be estimated from the available data).

Table 1: Adverse reactions of immediate-release exenatide identified from clinical trials andspontaneous reports

System organ class Frequency of occurrence/adverse reaction terms

Very Rare Very rare Notcommon Common Uncommon known

Blood and lymphaticsystem disorders

Drug-induced X3thrombocytopenia

Immune systemdisorders

Anaphylactic reaction X1

Metabolism andnutrition disorders

Hypoglycaemia (with X1metformin and asulphonylurea)2

Hypoglycaemia (with a X1sulphonylurea)

Decreased appetite X1

Dehydration, generally X1associated with nausea,vomiting and/ordiarrhoea.

Nervous systemdisorders

Headache2 X1

Dizziness X1

Dysgeusia X1

Somnolence X1

System organ class Frequency of occurrence/adverse reaction terms

Very Rare Very rare Notcommon Common Uncommon known

Gastrointestinaldisorders

Intestinal obstruction X1

Nausea X1

Vomiting X1

Diarrhoea X1

Dyspepsia X1

Abdominal pain X1

Gastroesophageal reflux X1disease

Abdominal distension X1

Acute pancreatitis (see X3section 4.4)

Eructation X1

Constipation X1

Flatulence X1

Delayed gastric emptying X1

Skin and subcutaneoustissue disorders

Hyperhidrosis2 X1

Alopecia X1

Macular and papular rash X3

Pruritus, and/ or urticaria X1

Angioneurotic oedema X3

Renal and urinarydisorders

Altered renal function, X1including acute renalfailure, worsened chronicrenal failure, renalimpairment, increasedserum creatinine

General disorders andadministration siteconditions

Feeling jittery X1

Asthenia 2 X1

Injection site reactions X1

Weight decreased X1

International normalised X3ratio increased withconcomitant warfarin,some reports associatedwith bleeding1 Rate based on immediate-release exenatide completed long-term efficacy and safety studies n=5763total (patients on sulphonylurea n=2971).2 In insulin-comparator controlled studies in which metformin and a sulphonylurea were concomitantmedicinal products, the incidence for these adverse reactions was similar for insulin- andimmediate-release exenatide-treated patients.3 Spontaneous reports data (unknown denominator)

When immediate-release exenatide was used in combination with basal insulin therapy the incidenceand types of other adverse events observed were similar to those seen in the controlled clinical trialswith exenatide as monotherapy, with metformin and/or sulphonylurea or a thiazolidinedione, with orwithout metformin.

Drug-induced thrombocytopenia

Drug-induced thrombocytopenia (DITP) with exenatide-dependent anti-platelet antibodies has beenreported 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 presenceof the sensitizing drug.

In studies in patients treated with immediate-release exenatide and a sulphonylurea (with or withoutmetformin), the incidence of hypoglycaemia was increased compared to placebo (23.5% and 25.2%versus 12.6% and 3.3%) and appeared to be dependent on the doses of both immediate-releaseexenatide and the sulphonylurea.

There were no clinically relevant differences in incidence or severity of hypoglycaemia with exenatidecompared to placebo, in combination with a thiazolidinedione, with or without metformin.

Hypoglycaemia was reported in 11% and 7% of patients treated with exenatide and placeborespectively.

Most episodes of hypoglycaemia were mild to moderate in intensity, and resolved with oraladministration of carbohydrate.

In a 30-week study, when immediate-release exenatide or placebo was added to existing basal insulintherapy (insulin glargine), the dose of basal insulin was decreased by 20% in patients with an HbA1c≤ 8.0%, per protocol design in order to minimize the risk of hypoglycaemia. Both treatment arms weretitrated to achieve target fasting plasma glucose levels (see section 5.1). There were no clinicallysignificant differences in the incidence of hypoglycaemic episodes in the immediate-release exenatidecompared to the placebo group (25% and 29% respectively). There were no episodes of majorhypoglycaemia in the immediate-release exenatide arm.

In a 24-week study, where either insulin lispro protamine suspension or insulin glargine was added toexisting therapy of immediate-release exenatide and metformin or metformin plus thiazolidinedionethe incidence of patients with at least one minor hypoglycaemic episode was 18% and 9% respectivelyand one patient reported major hypoglycaemia. In patients where existing therapy also included asulphonylurea the incidence of patients with at least one minor hypoglycaemic episode was 48% and54% respectively and one patient reported major hypoglycaemia.

Nausea

The most frequently reported adverse reaction was nausea. In patients treated with 5 mcg or 10 mcgimmediate-release exenatide, 36% reported at least one episode of nausea. Most episodes of nauseawere mild to moderate and occurred in a dose-dependent fashion. With continued therapy, thefrequency and severity decreased in most patients who initially experienced nausea.

The incidence of withdrawal due to adverse events was 8% for immediate-release exenatide-treatedpatients, 3% for placebo-treated and 1% for insulin-treated patients in the long-term controlled trials(16 weeks or longer). The most common adverse events leading to withdrawal for immediate-releaseexenatide-treated patients were nausea (4% of patients) and vomiting (1%). For placebo-treated orinsulin-treated patients, < 1% withdrew due to nausea or vomiting.

Immediate-release exenatide-treated patients in the open-label extension studies at 82 weeksexperienced similar types of adverse events observed in the controlled trials.

Injection site reactions have been reported in approximately 5.1% of subjects receivingimmediate-release exenatide in long-term (16 weeks or longer) controlled trials. These reactions haveusually been mild and usually did not result in discontinuation of immediate-release exenatide.

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals,patients may develop anti-exenatide antibodies following treatment with immediate-release exenatide.

In most patients who develop antibodies, antibody titres diminish over time and remain low through82 weeks.

Overall, the percentage of antibody positive patients was consistent across clinical trials. Patients whodevelop antibodies to exenatide tend to have more injection site reactions (for example: redness ofskin and itching), but otherwise similar rates and types of adverse events as those with no anti-exenatide antibodies. In the three placebo-controlled trials (n=963) 38% of patients had low titreanti-exenatide antibodies at 30 weeks. For this group, the level of glycaemic control (HbA1c) wasgenerally comparable to that observed in those without antibody titres. An additional 6% of patientshad higher titre antibodies at 30 weeks. About half of this 6% (3% of the total patients givenimmediate-release exenatide in the controlled studies), had no apparent glycaemic response toimmediate-release exenatide. In three insulin-comparator controlled trials (n=790) comparableefficacy and adverse events were observed in immediate-release exenatide-treated patients regardlessof antibody titre.

Examination of antibody-positive specimens from one long-term uncontrolled study revealed nosignificant cross-reactivity with similar endogenous peptides (glucagon or GLP-1).

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

Signs and symptoms of overdose may include severe nausea, severe vomiting and rapidly decliningblood glucose concentrations. In the event of overdose, appropriate supportive treatment (possiblygiven parenterally) should be initiated according to the patient’s clinical signs and symptoms.

Pharmacotherapeutic group: Glucagon-like peptide-1 (GLP-1) analogues, ATC code: A10BJ01.

Exenatide is a glucagon-like peptide-1 (GLP-1) receptor agonist that exhibits severalantihyperglycaemic actions of glucagon-like peptide-1 (GLP-1). The amino acid sequence ofexenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind to and activatethe known human GLP-1 receptor in vitro, its mechanism of action mediated by cyclic AMP and/orother intracellular signalling pathways.

Exenatide increases, on a glucose-dependent basis, the secretion of insulin from pancreatic beta cells.

As blood glucose concentrations decrease, insulin secretion subsides. When exenatide was used incombination with metformin alone, no increase in the incidence of hypoglycaemia was observed overthat of placebo in combination with metformin which may be due to this glucose-dependentinsulinotropic mechanism (see section 4.4).

Exenatide suppresses glucagon secretion which is known to be inappropriately elevated in type 2diabetes. Lower glucagon concentrations lead to decreased hepatic glucose output. However,exenatide does not impair the normal glucagon response and other hormone responses tohypoglycaemia.

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

Immediate-release exenatide improves glycaemic control through the immediate and sustained effectsof lowering both postprandial and fasting glucose concentrations in patients with type 2 diabetes.

Studies of immediate-release exenatide with metformin, a sulphonylurea or both as backgroundtherapy

The clinical studies comprised 3945 subjects (2997 treated with exenatide), 56% men and 44%women, 319 subjects (230 treated with exenatide) were ≥ 70 years of age and 34 subjects (27 treatedwith exenatide) were ≥ 75 years of age.

Immediate-release exenatide reduced HbA1c and body weight in patients treated for 30 weeks in threeplacebo-controlled studies, whether the immediate-release exenatide was added to metformin, asulphonylurea or a combination of both. These reductions in HbA1c were generally observed at12 weeks after initiation of treatment. See Table 2. The reduction in HbA1c was sustained and theweight loss continued for at least 82 weeks in the subset of 10 mcg BID patients completing both theplacebo-controlled studies and the uncontrolled study extensions (n=137).

Table 2: Combined results of the 30-week placebo-controlled studies (intent to treat patients)

Placebo Immediate-release Immediate-releaseexenatide 5 mcg BID exenatide 10 mcg

BID

N 483 480 483

Baseline HbA1c (%) 8.48 8.42 8.45

HbA1c (%) change from 0.08 -0.59 -0.89base line

Proportion of patients 7.9 25.3 33.6(%) achieving HbA1c≤ 7%

Proportion of patients 10.0 29.6 38.5(%) achieving HbA1c≤ 7% (patientscompleting studies)

Baseline weight (kg) 99.26 97.10 98.11

Change of weight from -0.65 -1.41 -1.91baseline (kg)

In insulin-comparator studies immediate-release exenatide (5 mcg BID for 4 weeks, followed by10 mcg BID) in combination with metformin and sulphonylurea significantly (statistically andclinically) improved glycaemic control, as measured by decrease in HbA1c. This treatment effect wascomparable to that of insulin glargine in a 26-week study (mean insulin dose 24.9 IU/day, range 4-95

IU/day, at the end of study) and biphasic insulin aspart in a 52-week study (mean insulin dose 24.4

IU/day, range 3-78 IU/day, at the end of study). Immediate-release exenatide lowered HbA1c from8.21 (n=228) and 8.6% (n=222) by 1.13 and 1.01% while insulin glargine lowered from 8.24 (n=227)by 1.10% and biphasic insulin aspart from 8.67 (n=224) by 0.86%. Weight loss of 2.3 kg (2.6%) wasachieved with immediate-release exenatide in the 26-week study and a loss of 2.5 kg (2.7%) in a52-week study whereas treatment with insulin was associated with weight gain. Treatment differences(immediate-release exenatide minus comparator) were -4.1 kg in the 26-week study and -5.4 kg in the52-week study. Seven-point self-monitored blood glucose profiles (before and after meals and at 3 am)demonstrated significantly reduced glucose values compared to insulin in the postprandial periodsafter immediate-release exenatide injection. Premeal blood glucose concentrations were generallylower in patients taking insulin compared to immediate-release exenatide. Mean daily blood glucosevalues were similar between immediate-release exenatide and insulin. In these studies the incidence ofhypoglycaemia was similar for immediate-release exenatide and insulin treatment.

Studies of immediate-release exenatide with metformin, a thiazolidinedione or both as backgroundtherapy

Two placebo-controlled studies were conducted: one of 16 and one of 26 weeks duration, with 121and 111 immediate-release exenatide and 112 and 54 placebo treated patients respectively, added toexisting thiazolidinedione treatment, with or without metformin. Of the immediate-release exenatidepatients, 12% were treated with a thiazolidinedione and immediate-release exenatide and 82% weretreated with a thiazolidinedione, metformin and immediate-release exenatide. Immediate-releaseexenatide (5 mcg BID for 4 weeks, followed by 10 mcg BID) resulted in statistically significantreductions from baseline HbA1c compared to placebo (-0.7% versus +0.1%) as well as significantreductions in body weight (-1.5 versus 0 kg) in the 16 week study. The 26-week study showed similarresults with statistically significant reductions from baseline HbA1c compared to placebo(-0.8% versus -0.1%). There was no significant difference in body weight between treatment groups inchange from baseline to endpoint (-1.4 versus -0.8 kg).

When immediate-release exenatide was used in combination with a thiazolidinedione, the incidence ofhypoglycaemia was similar to that of placebo in combination with a thiazolidinedione. The experiencein patients > 65 years and in patients with impaired renal function is limited. The incidence and type ofother adverse events observed were similar to those seen in the 30-week controlled clinical trials witha sulphonylurea, metformin or both.

Studies of immediate-release exenatide in combination with basal insulin

In a 30-week study, either immediate-release exenatide (5 mcg BID for 4 weeks, followed by 10 mcg

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 currentclinical practice to a target fasting plasma glucose of approximately 5.6 mmol/L. The mean age ofsubjects was 59 years and the mean duration of diabetes was 12.3 years.

At the end of the study, immediate-release exenatide (n=137) demonstrated a statistically significantreduction in the HbA1c and weight compared to placebo (n=122). Immediate-release exenatidelowered HbA1c by 1.7% from a baseline of 8.3% while placebo lowered HbA1c by 1.0% from abaseline of 8.5%. The proportion of patients achieving HbA1c < 7% and HbA1c ≤ 6.5% was 56% and42% with immediate-release exenatide and 29% and 13% with placebo. Weight loss of 1.8 kg from abaseline of 95 kg was observed with immediate-release exenatide whereas a weight gain of 1.0 kgfrom a baseline of 94 kg was observed with placebo.

In the immediate-release exenatide arm the insulin dose increased by 13 units/day compared to20 units/day on the placebo arm. Immediate-release exenatide reduced fasting serum glucose by1.3 mmol/L and placebo by 0.9 mmol/L. The immediate-release exenatide arm compared to placebohad significantly lowered postprandial blood glucose excursions at the morning meal(- 2.0 versus - 0.2 mmol/L) and evening meal (- 1.6 versus + 0.1 mmol/L), there was no differencebetween treatments at midday.

In a 24-week study, where either insulin lispro protamine suspension or insulin glargine was added toexisting therapy of immediate-release exenatide and metformin, metformin and sulphonylurea ormetformin and pioglitazone, HbA1c was lowered by 1.2% (n=170) and by 1.4% (n=167) respectivelyfrom a baseline of 8.2%. Weight increase of 0.2 kg was observed for patients on insulin lisproprotamine suspension and 0.6 kg for insulin glargine treated patients from a baseline of 102 kg and103 kg respectively.

In a 30-week, open-label, active comparator-controlled, noninferiority study, the safety and efficacy ofimmediate-release exenatide (n=315) versus titrated insulin lispro three times daily (n=312) on abackground of optimized basal insulin glargine and metformin in patients with type 2 diabetes wasevaluated.

Following a basal insulin optimization (BIO) phase, patients with HbA1c 7.0% were randomized toadd either immediate-release exenatide or insulin lispro to their existing regimen of insulin glargineand metformin. In both treatment groups, subjects continued to titrate their insulin glargine dosesusing an algorithm reflecting current clinical practice.

All patients assigned to immediate-release exenatide initially received 5 mcg BID for four weeks.

After four weeks, their dose was increased to 10 mcg BID. Patients in the immediate-releaseexenatide-treated group with an HbA1c  8.0% at the end of the BIO phase decreased their insulinglargine dose by at least 10%.

Immediate-release exenatide lowered HbA1c by 1.1% from a baseline of 8.3% and insulin lisprolowered HbA1c by 1.1% from a baseline of 8.2% and noninferiority of immediate-release exenatide totitrated lispro was demonstrated. The proportion of patients achieving HbA1c < 7% was 47.9% withimmediate-release exenatide and 42.8% with insulin lispro. Weight loss of 2.6 kg from a baseline of89.9 kg was observed with immediate-release exenatide whereas a weight gain of 1.9 kg from abaseline of 89.3 kg was observed with insulin lispro.

Fasting lipids

Immediate-release exenatide has shown no adverse effects on lipid parameters. A trend for a decreasein triglycerides has been observed with weight loss.

Beta-cell function

Clinical studies with immediate-release exenatide have indicated improved beta-cell function, usingmeasures such as the homeostasis model assessment for beta-cell function (HOMA-B) and theproinsulin to insulin ratio.

A pharmacodynamic study demonstrated in patients with type 2 diabetes (n=13) a restoration of firstphase insulin secretion and improved second phase insulin secretion in response to an intravenousbolus of glucose.

A reduction in body weight was seen in patients treated with immediate-release exenatide irrespectiveof the occurrence of nausea although the reduction was larger in the group with nausea (meanreduction 2.4 kg versus 1.7 kg) in the long-term controlled studies of up to 52 weeks.

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

The efficacy and safety of immediate release exenatide was evaluated in a 28-week randomized,double-blind, placebo controlled study conducted in 120 patients aged 10 to 17 years with type 2diabetes who had HbA1c 6.5% to 10.5% and who were either naive to anti-diabetes agents or weretreated with metformin alone, a sulfonylurea alone, or metformin in combination with a sulfonylurea.

Patients received twice daily treatment with immediate release exenatide 5 µg, immediate releaseexenatide 10 µg or equivalent dose of placebo for 28 weeks. The primary efficacy endpoint was thechange in HbA1c from baseline to 28 weeks of treatment; the treatment difference (pooled doses) fromplacebo was not statistically significant [-0.28% (95% CI: -1.01, 0.45)]. No new safety findings wereidentified in this paediatric study.

Following subcutaneous administration to patients with type 2 diabetes, exenatide reaches medianpeak plasma concentrations in 2 h. Mean peak exenatide concentration (Cmax) was 211 pg/mL andoverall mean area under the curve (AUC0-inf) was 1036 pg h/mL following subcutaneousadministration of a 10 mcg dose of exenatide. Exenatide exposure increased proportionally over thetherapeutic dose range of 5 mcg to 10 mcg. Similar exposure is achieved with subcutaneousadministration of exenatide in the abdomen, thigh, or arm.

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

Nonclinical studies have shown that exenatide is predominantly eliminated by glomerular filtrationwith subsequent proteolytic degradation. In clinical studies the mean apparent clearance of exenatideis 9 L/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatideare independent of the dose.

In patients with mild (creatinine clearance 50 to 80 mL/min) or moderate renal impairment (creatinineclearance 30 to 50 mL/min), exenatide clearance was mildly reduced compared to clearance inindividuals with normal renal function (13% reduction in mild and 36% reduction in moderate renalimpairment). Clearance was significantly reduced by 84% in patients with end-stage renal diseasereceiving dialysis (see section 4.2).

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

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

Long-term controlled data in elderly are limited, but suggest no marked changes in exenatide exposurewith increased age up to about 75 years old. In a pharmacokinetic study in patients with type 2diabetes, administration of exenatide (10 mcg) 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 toreduced renal function in the older age group (see section 4.2).

In a single-dose pharmacokinetic study in 13 patients with type 2 diabetes and between the ages of 12and 16 years, administration of exenatide (5 mcg) resulted in slightly lower mean AUC (16% lower)and Cmax (25% lower) compared to those observed in adults.

Non-clinical data reveal no special hazards for humans based on conventional studies of safetypharmacology, repeat-dose toxicity, or genotoxicity.

In female rats given exenatide for 2 years, an increased incidence of benign thyroid C-cell adenomaswas observed at the highest dose, 250 mcg/kg/day, a dose that produced an exenatide plasma exposure130-fold the human clinical exposure. This incidence was not statistically significant when adjustedfor survival. There was no tumorigenic response in male rats or either sex of mice.

Animal studies did not indicate direct harmful effects with respect to fertility or pregnancy. High dosesof exenatide during mid-gestation caused skeletal effects and reduced foetal growth in mice andreduced foetal growth in rabbits. Neonatal growth was reduced in mice exposed to high doses duringlate gestation and lactation.

metacresolmannitolglacial acetic acidsodium acetate trihydratewater for injections

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

3 years

In use pen:30 days

Store in a refrigerator (2 ºC - 8 ºC).

Do not freeze.

In use pen:

Store below 25 ºC.

The pen must not be stored with the needle attached.

Replace cap on pen in order to protect from light.

Type I glass cartridge with a (bromobutyl) rubber plunger, rubber disc, and aluminium seal. Eachcartridge is assembled into a disposable pen-injector (pen).

5 mcg: Each pre-filled pen contains 60 doses (approximately 1.2 mL of solution).10 mcg: Each pre-filled pen contains 60 doses (approximately 2.4 mL of solution).

Pack size of 1 and 3 pens. Not all pack sizes may be marketed.

Injection needles are not included.

Becton, Dickinson and Company needles are suitable to use with the Byetta pen.

The patient should be instructed to discard the needle after each injection.

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

Byetta is for use by one person only.

The instructions for using the pen, included with the leaflet, must be followed carefully.

The pen must not be stored with the needle attached.

Byetta should not be used if particles appear or if the solution is cloudy and/or coloured.

Do not use Byetta if it has been frozen.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/06/362/001 -4

Date of first authorisation: 20 November 2006

Date of latest renewal: 22 July 2016

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

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