BYETTA* 5 micrograms solution for injection, pre-filled pen.

BYETTA10 micrograms solution for injection, pre-filled pen.

Each dose contains 5 micrograms (μg) exenatide in 20 microlitres (μl), (0.25 mg exenatide per ml).

Excipients: Each dose contains 44 µg metacresol.

Each dose contains 10 micrograms (μg) exenatide in 40 microlitres (μl), (0.25 mg exenatide per ml).

Excipients: Each dose contains 88 µg metacresol.

For a full list of excipients, see section 6.1.

Solution for injection, pre-filled pen.

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 thiazolidinedione

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

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

Posology

BYETTA therapy should be initiated at 5 μg exenatide per dose, administered twice daily (BID), for at least one month in order to improve tolerability. The dose of exenatide can then be increased to 10 μg BID to further improve glycaemic control. Doses higher than 10 µg BID are not recommended.

BYETTA is available as either a 5 µg or a 10 µg exenatide per dose pre-filled pen.

BYETTA can be administered at any time within the 60-minute period before the morning and evening meal (or two main meals of the day, approximately 6 hours or more apart). BYETTA should not be administered after a meal. If an injection is missed, the treatment should be continued with the next scheduled dose.

BYETTA is recommended for use in patients with Type 2 diabetes mellitus who are already receiving metformin, a sulphonylurea, pioglitazone and/or a basal insulin. One can continue to use BYETTA when a basal insulin is added to existing therapy. When BYETTA is added to existing metformin and/or pioglitazone therapy, the current dose of metformin and/or pioglitazone can be continued as no increased risk of hypoglycaemia is anticipated, compared to metformin or pioglitazone alone. When BYETTA is added to sulphonylurea therapy, a reduction in the dose of sulphonylurea should be considered to reduce the risk of hypoglycaemia (see section 4.4). When BYETTA is used in combination with basal insulin, the dose of basal insulin should be evaluated. In patients at increased risk of hypoglycaemia consider reducing the dose of basal insulin (see section 4.8).

The dose of BYETTA does not need to be adjusted on a day-by-day basis depending on self-monitored glycaemia. However, blood glucose self-monitoring may become necessary to adjust the dose of sulphonylureas or the dose of basal insulin.

Special populations

Elderly

BYETTA should be used with caution, and dose escalation from 5 µg to 10 µg should proceed conservatively in patients >70 years. The clinical experience in patients >75 years is very limited.

Patients with renal impairment

No dosage adjustment of BYETTA is necessary in patients with mild renal impairment (creatinine clearance 50-80 ml/min).

In patients with moderate renal impairment (creatinine clearance 30-50 ml/min), dose escalation from 5 µg to 10 µg should proceed conservatively (see section 5.2).

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

Patients with hepatic impairment

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

Paediatric population

The safety and effectiveness of exenatide have not been established in patients under 18 years of age (see section 5.2). Currently available data are described in section 5.2 but no recommendation on a posology can be made.

Method of administration

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

BYETTA and basal insulin must be administered as two separate injections.

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

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

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

BYETTA must not be administered by intravenous or intramuscular injection.

Renal impairment

In patients with end-stage renal disease receiving dialysis, single doses of BYETTA 5 μg increased frequency and severity of gastrointestinal adverse reactions. BYETTA is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance <30 ml/min). The clinical experience in patients with moderate renal impairment is very limited (see section 4.2).

There have been rare, spontaneously reported events of altered renal function, including increased serum creatinine, renal impairment, worsened chronic renal failure and acute renal failure, sometimes requiring haemodialysis. Some of these events occurred in patients experiencing events that may affect hydration, including nausea, vomiting, and/or diarrhoea, and/or receiving medicinal products known to affect renal function/hydration status. Concomitant medicinal products included angiotensin converting enzymes inhibitors, angiotensin-II antagonists, non-steroidal anti-inflammatory medicinal products and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative medicinal products, including BYETTA.

Severe gastrointestinal disease

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

Acute pancreatitis

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

Concomitant medicinal products

The effect of BYETTA to slow gastric emptying may reduce the extent and rate of absorption of orally administered medicinal products. BYETTA should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption and medicinal products with a narrow therapeutic ratio. Specific recommendations regarding intake of such medicinal products in relation to BYETTA is given in section 4.5.

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

Patients with BMI 25

The experience in patients with BMI 25 is limited.

Rapid weight loss

Weight loss greater than 1.5 kg per week has been observed in approximately 5% of clinical trial patients treated with exenatide. Weight loss of this rate may have harmful consequences.

Hypoglycaemia

When BYETTA was used in combination with a sulphonylurea, the incidence of hypoglycaemia was increased over that of placebo in combination with a sulphonylurea. In the clinical studies, patients on a sulphonylurea combination, with mild renal impairment, had an increased incidence of hypoglycaemia compared to patients with normal renal function. To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea should be considered.

Excipients

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

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

The effect of BYETTA to slow gastric emptying may reduce the extent and rate of absorption of orally administered medicinal products. Patients receiving medicinal products of either a narrow therapeutic ratio or medicinal products that require careful clinical monitoring should be followed closely. These medicinal products should be taken in a standardised way in relation to BYETTA injection. If such medicinal products are to be administered with food, patients should be advised to, if possible, take them with a meal when BYETTA is not 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 before BYETTA injection.

Gastro-resistant formulations containing substances sensitive for degradation in the stomach, such as proton pump inhibitors, should be taken at least 1 hour before or more than 4 hours after BYETTA injection.

Digoxin, lisinopril and warfarin

A delay in T_max of about 2 h was observed when digoxin, lisinopril or warfarin was administered 30 min after exenatide. No clinically relevant effects on C_max or AUC were observed. However, since market introduction, increased INR (International Normalized Ratio) has been reported during concomitant use of warfarin and BYETTA. INR should be closely monitored during initiation and dose increase of BYETTA therapy in patients on warfarin and/or cumarol derivatives (see section 4.8).

Metformin or sulphonylureas

BYETTA is not expected to have any clinically relevant effects on the pharmacokinetics of metformin or sulphonylureas. Hence no restriction in timing of intake of these medicinal products in relation to BYETTA injection are needed.

Paracetamol

Paracetamol was used as a model medicinal product to evaluate the effect of exenatide on gastric emptying. When 1,000 mg paracetamol was given with 10 µg BYETTA (0 h) and 1 h, 2 h, and 4 h after BYETTA injection, paracetamol AUCs were decreased by 21%, 23%, 24%, and 14%, respectively; C_max was decreased by 37%, 56%, 54%, and 41%, respectively; T_max 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, C_max, and T_max were not significantly changed when paracetamol was given 1 hour before BYETTA injection. No adjustment to paracetamol dosing is required based on these study results.

Hydroxy Methyl Glutaryl Coenzyme A (HMG CoA) reductase inhibitors

Lovastatin AUC and C_max were decreased approximately 40% and 28%, respectively, and T_max was delayed about 4 h when BYETTA (10 μg 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 BYETTA and HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles (see section 5.1). 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.

Ethinyl Oestradiol and Levonorgestrel

Administration of a combination oral contraceptive (30µg ethinyl oestradiol plus 150µg levonorgestrel) one hour before BYETTA (10 µg BID) did not alter the AUC, C_max or C_min of either ethinyl oestradiol or levonorgestrel. Administration of the oral contraceptive 30 minutes after BYETTA did not affect AUC but resulted in a reduction of the C_max of ethinyl oestradiol by 45%, and C_max of levonorgestrel by 27-41%, and a delay in T_max by 2-4 h due to delayed gastric emptying. The reduction in C_max is of limited clinical relevance and no adjustment of dosing of oral contraceptives is required.

Women of childbearing potential

If a patient wishes to become pregnant, or pregnancy occurs, treatment with BYETTA should be discontinued.

Pregnancy

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

Breastfeeding

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

Fertility

No fertility studies in humans have been conducted.

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

Summary of the safety profile

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

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

Tabulated list of adverse reactions

Table 1 lists adverse reactions reported from Phase 3 studies. The table presents adverse reactions that occurred with an incidence 5% and more frequently among BYETTA-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 2X incidence among BYETTA-treated patients than insulin- or placebo-treated patients.

The reactions are listed below as MedDRA preferred term by system organ class and absolute frequency. Patient frequencies are defined as: very common (1/10), common (1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data), including isolated reports.

Table 1 Adverse Reactions Reported in Long-Term Phase 3 Controlled Studies¹and spontaneous adverse reactions³

¹ Data from Phase 3 comparator-controlled studies versus placebo, insulin glargine or 30% soluble insulin aspart/70% insulin aspart protamine crystals (biphasic insulin aspart) in which patients also received metformin, thiazolidinediones or sulphonylurea in addition to BYETTA or comparator.

(N= 1788 BYETTA-treated intent-to-treat (ITT) patients.)

² In insulin-comparator controlled studies in which metformin and a sulphonylurea were concomitant medicinal products, the incidence for these adverse reactions was similar for insulin- and BYETTA-treated patients.

³ Post-marketing reports

When BYETTA was used in combination with basal insulin therapy the incidence and types of other adverse events observed were similar to those seen in the controlled clinical trials with exenatide as monotherapy, with metformin and/or sulphonylurea or a thiazolidinedione, with or without metformin.

Description of selected adverse reactions

Hypoglycaemia

In studies in patients treated with BYETTA and a sulphonylurea (with or without metformin), 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 BYETTA and the sulphonylurea.

There were no clinically relevant differences in incidence or severity of hypoglycaemia with exenatide compared to placebo, in combination with a thiazolidinedione, with or without metformin. Hypoglycaemia was reported in 11% and 7% of patients treated with exenatide and placebo respectively.

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

In a 30-week study, when BYETTA or placebo was added to existing basal insulin therapy (insulin glargine), the dose of basal insulin was decreased by 20 % in patients with an HbA_1c 8.0 %, per protocol design in order to minimize the risk of hypoglycaemia. Both treatment arms were titrated to achieve target fasting plasma glucose levels (see section 5.1). There were no clinically significant differences in the incidence of hypoglycaemic episodes in the BYETTA compared to the placebo group (25% and 29% respectively). There were no episodes of major hypoglycaemia in the BYETTA arm.

In a 24-week study, where either insulin lispro protamine suspension or insulin glargine was added to existing therapy of BYETTA and metformin or metformin plus thiazolidinedione the incidence of patients with at least one minor hypoglycaemic episode was 18% and 9% respectively and one patient reported major hypoglycaemia. In patients where existing therapy also included a sulphonylurea the incidence of patients with at least one minor hypoglycaemic episode was 48% and 54% respectively and one patient reported major hypoglycaemia.

Nausea

The most frequently reported adverse reaction was nausea. In patients treated with 5 µg or 10 µg BYETTA, generally 40-50% reported at least one episode of nausea. Most episodes of nausea were mild to moderate and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea.

The incidence of withdrawal due to adverse events was 8% for BYETTA-treated patients, 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 BYETTA-treated patients were nausea (4% of patients) and vomiting (1%). For placebo-treated or insulin-treated patients, <1% withdrew due to nausea or vomiting.

BYETTA-treated patients in the open-label extension studies at 82 weeks experienced similar types of adverse events observed in the controlled trials.

Injection-site reactions

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

Immunogenicity

Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-exenatide antibodies following treatment with BYETTA. In most patients who develop antibodies, antibody titres diminish over time and remain low through 82 weeks.

Overall, the percentage of antibody positive patients was consistent across clinical trials. Patients who develop antibodies to exenatide tend to have more injection-site reactions (for example: redness of skin and itching), but otherwise similar rates and types of adverse events as those with no anti-exenatide antibodies. In the three placebo-controlled trials (n = 963), 38% of patients had low titre anti-exenatide antibodies at 30 weeks. For this group, the level of glycaemic control (HbA_1c) was generally comparable to that observed in those without antibody titres. An additional 6% of patients had higher titre antibodies at 30 weeks. About half of this 6% (3% of the total patients given BYETTA in the controlled studies) had no apparent glycaemic response to BYETTA. In two insulin-comparator controlled trials (n = 475), comparable efficacy and adverse events were observed in BYETTA-treated patients regardless of antibody titre.

Examination of antibody-positive specimens from one long-term uncontrolled study revealed no significant cross-reactivity with similar endogenous peptides (glucagon or GLP-1).

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

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

Mechanism of action

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

Exenatide increases, on a glucose-dependent basis, the secretion of insulin from pancreatic beta cells. As blood glucose concentrations decrease, insulin secretion subsides. When exenatide was used in combination with metformin alone, no increase in the incidence of hypoglycaemia was observed over that of placebo in combination with metformin, which may be due to this glucose-dependent insulinotropic mechanism (see section 4.4).

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

BYETTA improves glycaemic control through the immediate and sustained effects of lowering both postprandial and fasting glucose concentrations in patients with Type 2 diabetes.

Clinical efficacy

Studies of BYETTA with metformin, a sulphonylurea or both as background therapy

The clinical studies comprised 3,945 subjects (2,997 treated with exenatide), 56% men and 44% women; 319 subjects (230 treated with exenatide) were 70 years of age and 34 subjects (27 treated with exenatide) were 75 years of age.

BYETTA reduced HbA_1c and body weight in patients treated for 30 weeks in three placebo-controlled studies, whether the BYETTA was added to metformin, a sulphonylurea or a combination of both. These reductions in HbA_1c were generally observed at 12 weeks after initiation of treatment. See Table 2. The reduction in HbA_1c was sustained, and the weight loss continued for at least 82 weeks in the subset of 10 µg BID patients completing both the placebo-controlled studies and the uncontrolled study extensions (n = 137).

Table 2 Combined Results of the 30-Week Placebo-Controlled Studies (Intent-to-Treat Patients)

In insulin-comparator studies, BYETTA (5µg BID for 4 weeks, followed by 10µg BID), in combination with metformin and sulphonylurea, significantly (statistically and clinically) improved glycaemic control, as measured by decrease in HbA_1c. This treatment effect was comparable 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 24.4IU/day, range 3-78IU/day, at the end of study). BYETTA lowered HbA_1c from 8.21 (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%) was achieved with BYETTA in the 26-week study and a loss of 2.5 kg (2.7%) in a 52-week study, whereas treatment with insulin was associated with weight gain. Treatment differences (BYETTA minus comparator) were -4.1 kg in the 26-week study and -5.4 kg in the 52-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 periods after BYETTA injection. Pre-meal blood glucose concentrations were generally lower in patients taking insulin compared to BYETTA. Mean daily blood glucose values were similar between BYETTA and insulin. In these studies, the incidence of hypoglycaemia was similar for BYETTA and insulin treatment.

Studies of BYETTA with metformin, a thiazolidinedione or both as background therapy

Two placebo-controlled studies were conducted: one of 16 and one of 26 weeks duration, with 121 and 111 BYETTA and 112 and 54 placebo-treated patients respectively, added to existing thiazolidinedione treatment, with or without metformin. Of the BYETTA patients, 12% were treated with a thiazolidinedione and BYETTA and 82% were treated with a thiazolidinedione, metformin and BYETTA. BYETTA (5 µg BID for 4 weeks, followed by 10 µg BID) resulted in statistically significant reductions from baseline HbA_1c compared to placebo (-0.7% versus +0.1%) as well as significant reductions in body weight (-1.5 versus 0 kg) in the 16-week study. The 26-week study showed similar results with statistically significant reductions from baseline HbA_1c compared to placebo (-0.8% versus -0.1%). There was no significant difference in body weight between treatment groups in change from baseline to endpoint (-1.4 versus -0.8 kg).

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

Studies of BYETTA in combination with basal insulin

In a 30-week study, either BYETTA (5 µg BID for 4 weeks, followed by 10 µg 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, BYETTA (n=137) demonstrated a statistically significant reduction in the HbA_1c and weight compared to placebo (n=122). BYETTA lowered HbA_1c by 1.7 % from a baseline of 8.3 % while placebo lowered HbA_1c by 1.0 % from a baseline of 8.5 %. The proportion of patients achieving HbA_1c <7% and HbA_1c6.5% was 56 % and 42 % with BYETTA and 29 % and 13 % with placebo. Weight loss of 1.8 kg from a baseline of 95 kg was observed with BYETTA whereas a weight gain of 1.0 kg from a baseline of 94kg was observed with placebo.

In the BYETTA arm the insulin dose increased by 13 units/day compared to 20 units/ day on the placebo arm. BYETTA reduced fasting serum glucose by 1.3 mmol/l and placebo by 0.9 mmol/l. BYETTA arm compared to placebo had 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 difference between treatments at midday.

In a 24-week study, where either insulin lispro protamine suspension or insulin glargine was added to existing therapy of BYETTA and metformin, metformin and sulphonylurea or metformin and pioglitazone, HbA1c was lowered by 1.2 % (n=170) and by 1.4 % (n=167) respectively from a baseline of 8.2 %. Weight increase of 0.2 kg was observed for patients on insulin lispro protamine suspension and 0.6 kg for insulin glargine-treated patients from a baseline of 102 kg and 103 kg respectively.

Fasting lipids

BYETTA has shown no adverse effects on lipid parameters. A trend for a decrease in triglycerides has been observed with weight loss.

Beta-cell function

Clinical studies with BYETTA have indicated improved beta-cell function, using measures such as the homeostasis model assessment for beta-cell function (HOMA-B) and the proinsulin to insulin ratio. A pharmacodynamic study demonstrated, in patients with Type 2 diabetes (n = 13), a restoration of first-phase insulin secretion and improved second-phase insulin secretion in response to an intravenous bolus of glucose.

Body weight

A reduction in body weight was seen in patients treated with BYETTA irrespective of the occurrence of nausea, although the reduction was larger in the group with nausea (mean reduction 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 and increased satiety.

Paediatric population

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

Absorption

Following subcutaneous administration to patients with Type 2 diabetes, exenatide reaches median peak plasma concentrations in 2 h. Mean peak exenatide concentration (C_max) was 211 pg/ml and overall mean area under the curve (AUC_0-inf) was 1036 pg •h/ml following subcutaneous administration of a 10 μg dose of exenatide. Exenatide exposure increased proportionally over the therapeutic dose range of 5 μg to 10 μg. Similar exposure is achieved with subcutaneous administration of exenatide in the abdomen, thigh, or arm.

Distribution

The mean apparent volume of distribution of exenatide following subcutaneous administration of a single dose of exenatide is 28 l.

Biotransformation and elimination

Non-clinical studies have shown that exenatide is predominantly eliminated by glomerular filtration, with subsequent proteolytic degradation. In clinical studies, the mean apparent clearance of exenatide is 9 l/h and the mean terminal half-life is 2.4 h. These pharmacokinetic characteristics of exenatide are independent of the dose.

Special Populations

Patients with renal impairment

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

Patients with hepatic insufficiency

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

Gender and race

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

Elderly

Long-term controlled data in elderly are limited, but suggest no marked changes in exenatide exposure with increased age up to about 75 years old. In a pharmacokinetic study in patients with Type 2 diabetes, administration of exenatide (10 µg) resulted in a mean increase of exenatide AUC by 36% in 15 elderly subjects aged 75 to 85 years compared to 15 subjects aged 45 to 65 years likely related to reduced renal function in the older age group (see section 4.2).

Paediatric population

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

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

In female rats given exenatide for 2 years, an increased incidence of benign thyroid C-cell adenomas was observed at the highest dose, 250 µg/kg/day, a dose that produced an exenatide plasma exposure 130-fold the human clinical exposure. This incidence was not statistically significant when adjusted for 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 doses of exenatide during mid-gestation caused skeletal effects and reduced foetal growth in mice and reduced foetal growth in rabbits. Neonatal growth was reduced in mice exposed to high doses during late gestation and lactation.

Metacresol

Mannitol

Glacial acetic acid

Sodium acetate trihydrate

Water for injections

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

3 years.

Shelf life for pen in use: 30 days.

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

In use

Store below 25 °C.

The pen should 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. Each cartridge is assembled into a disposable pen-injector (pen).

Each pre-filled pen contains 60 doses of sterile preserved solution (approximately 1.2 ml [5 μg] or 2.4 ml [10 μg]).

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

Injection needles are not included. The following are examples of disposable needles that can be used with the BYETTA pen: 29, 30, or 31 gauge (diameter 0.25-0.33 mm) and 12.7, 8, or 5 mm length.

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 local requirements.

Instructions for use

BYETTA is for use by one person only.

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

The pen is stored without needle.

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

BYETTA that has been frozen must not be used.

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

EU/1/06/362/001: 5 μg (1 pen)

EU/1/06/362/002: 5 μg (3 pens)

EU/1/06/362/003: 10 μg (1 pen)

EU/1/06/362/004: 10 μg (3 pens)

Date of first authorisation: 20 November 2006

Date of latest renewal: 20 November 2011

19 March 2012

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

POM

*BYETTA (exenatide) is a trademark of Amylin Pharmaceuticals, Inc. BY10M