Eli Lilly and Company Limited

Changes

Following the renewal of the Byetta marketing authorisation, the SmPC has been updated in its entirety.

Of  note:

4.1.      Therapeutic indications

There is a minor change to the indication wording from 'patients' to 'adults'.

4.8.      Undesirable effects

Spontaneous adverse reaction frequencies are now presented in table 1.

 10.       DATE OF REVISION OF THE TEXT

New date

 19 September 2011

4.         Clinical particulars

4.1       Therapeutic indications

Added (bold):

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

4.2       Posology and method of administration

Added (bold) deleted (strikethrough):

BYETTA is recommended for use in patients with type 2 diabetes mellitus who are already receiving metformin, and/or a sulphonylurea or a thiazolidinedione. When BYETTA is added to existing metformin and/or thiazolidinedione therapy, the current dose of metformin and/or thiazolidinedione can be continued as no increased risk of hypoglycaemia is anticipated, compared to metformin or thiazolidinedione alone.

Deleted:

Limited experience exists concerning the combination of BYETTA with thiazolidinediones (see section 5.1).

4.8       Undesirable effects

Added:

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.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

Added (bold) deleted (strikethrough):

In aTwo placebo-controlled studies were conducted: one of 16 and one of 26 weeks duration, with 121 and 111 BYETTA and 112 and 54(n=121) or placebo treated patients respectively(n=112) was, 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 -0.2 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.

Added:

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).

10.          DATE OF REVISION OF THE TEXT

                New date

06 August 2010

Changes

Addition text underlined in red.

4.            Clinical particulars

4.4          Special warnings and precautions for use

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

BYETTA should not be used in Type 2 diabetes patients who require insulin therapy due to beta-cell failure.

Intravenous or intramuscular injection of BYETTA is not recommended.

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

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 pharmacological agents known to affect renal function/hydration status. Concomitant agents included angiotensin converting enzymes inhibitors, angiotensin-II antagonists, nonsteroidal anti-inflammatory medicinal products and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative agents, including BYETTA.

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.

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

The concurrent use of BYETTA with insulin, D-phenylalanine derivatives (meglitinides), or alpha-glucosidase inhibitors has not been studied and cannot be recommended.

The experience in patients with BMI ≤25 is limited.

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

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.

Interactions

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.

4.8          Undesirable effects

Table 1 lists adverse reactions reported from Phase 3 studies.  The table presents adverse reactions that occurred with an incidence ³5% and more frequently among BYETTA-treated patients than insulin- or placebo-treated patients.  The table also includes adverse reactions that occurred with an incidence ³1% and with a statistically significantly higher and/or ³2X 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, <1/10) and uncommon (³1/1,000 to <1/100).

Table 1 Adverse Reactions Reported in Long-Term Phase 3 Controlled Studies¹

n = 1,788 BYETTA-treated intent-to-treat (ITT) patients.

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.

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 Does not conform to criteria previously cited; acute pancreatitis events were uncommon in all treatment groups.

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

Nausea

The most frequently reported adverse reaction was nausea.  In patients treated with 5µg or 10µg 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 developed anti-exenatide antibodies to exenatide 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 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).

Spontaneous Reports

Since market introduction of BYETTA, the following additional adverse reactions have been reported:

Immune system disorders: Anaphylactic reaction, very rarely.

Metabolism and nutritional disorders: Dehydration, generally associated with nausea, vomiting and/or diarrhoea.

Nervous system disorders: Dysgeusia, somnolence.

Gastrointestinal disorders: Eructation, constipation, flatulence.

Renal and urinary disorders: Altered renal function, including acute renal failure, worsened chronic renal failure, renal impairment, increased serum creatinine (see section 4.4).

Skin and subcutaneous tissue disorders: alopecia (rarely), macular rash, papular rash, pruritus, urticaria, angioneurotic oedema.

Investigations: International normalised ratio increased with concomitant warfarin, some reports associated with bleeding (see section 4.5).

5.             PHARMACOLOGICAL PROPERTIES

5.1          Pharmacodynamic properties

Pharmacotherapeutic group: Other blood glucose lowering drugs, excl. insulins. ATC code: A10BX04.

Mechanism of Action

Exenatide is an incretin mimetic 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

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 10µg 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 a placebo-controlled study of 16 weeks duration, BYETTA (n = 121) or placebo (n = 112) was added to existing thiazolidinedione treatment, with or without metformin.  BYETTA (5µg BID for 4 weeks, followed by 10µg BID) resulted in statistically significant reductions from base line HbA_1c compared to placebo (-0.8% versus +0.1%), as well as significant reductions in body weight (-1.5 versus -0.2 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.

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 24.9IU/day, range 4-95IU/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.  Premeal 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.

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

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.

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.

5.2              Pharmacokinetic properties

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.

Metabolism and Elimination

Nonclinical 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 Ddata in elderly are limited, but suggest no marked changes in exenatide exposure with increased age up to about 75 years old. There are no pharmacokinetic data in patients >75 years.

In a pharmacokinetic study in patients with type 2 diabetes, administration of exenatide (10µg) 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).

Children and adolescents

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 (5mg) resulted in slightly lower mean AUC (16% lower) and Cmax (25% lower) compared to those observed in adults.

6. PHARMACEUTICAL PARTICULARS

6.3       Shelf life

 3  2 years.

Shelf life for pen in use: 30 days.

10.          DATE OF REVISION OF THE TEXT

                New date

15 March 2010

4.            Clinical particulars

4.4          Special warnings and precautions for use

Added (bold):

There have been rare, spontaneously reported events of acute pancreatitis. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed with supportive treatment but very rare cases of necrotizing or hemorrhagic 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.

4.8          Undesirable effects

Added (bold):

common (≥1/100, <1/10) and uncommon (³1/1,000 to <1/100).

Table changed in entirety:

Added:

³ Does not conform to criteria previously cited; acute pancreatitis events were uncommon in all treatment groups.

Deleted:

Gastrointestinal disorders: eructation, constipation, flatulence, acute pancreatitis (see section 4.4).

10.          DATE OF REVISION OF THE TEXT

                New date

06 March 2009

4.         Clinical particulars

4.2       Posology and method of administration

Added (bold) Deleted (strikethrough)

Children and adolescents: The safety and effectiveness of exenatide have not been established in patients under 18 years of age. (see section 5.2). There is no experience in children and adolescents below 18 years.

5.         PHARMACOLOGICAL PROPERTIES

5.1       Pharmacodynamic properties

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

Changed (bold):

5.2       Pharmacokinetic properties

Added (Bold) Deleted (strikethrough):

Children and adolescents: 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 (5mg) resulted in slightly lower mean AUC (16% lower) and Cmax (25% lower) compared to those observed in adults. Pharmacokinetics of exenatide has not been investigated in children and adolescents below 18 years of age.

10.       DATE OF REVISION OF THE TEXT

                New date

07 January 2009

4.         Clinical particulars

4.4          Special warnings and precautions for use

Added paragraphs:

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 hemodialysis. Some of these events occurred in patients experiencing events that may affect hydration, including nausea, vomiting, and/or diarrhoea and/or receiving pharmacological agents known to affect renal function/hydration status. Concomitant agents included angiotensin converting enzymes inhibitors, angiotensin-II antagonists, nonsteroidal anti-inflammatory medicinal products and diuretics. Reversibility of altered renal function has been observed with supportive treatment and discontinuation of potentially causative agents, including BYETTA.

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. If pancreatitis is suspected, BYETTA and other potentially suspect medicinal products should be discontinued.

4.8       Undesirable effects

Spontaneous reports

Deleted (bold text):

Metabolism and nutritional disorders: Dehydration, generally associated with nausea, vomiting and/or diarrhoea, some reports associated with elevation of serum creatinine.

Added (bold text):

Gastrointestinal disorders: eructation, constipation, flatulence, acute pancreatitis (see section 4.4).

Added:

Renal and urinary disorders: altered renal function, including acute renal failure, worsened chronic renal failure, renal impairment, increased serum creatinine (see section 4.4).

10.          DATE OF REVISION OF THE TEXT

                New date

28 January 2008

4.             Clinical particulars

4.5          Interaction with other medicinal products and other forms of interaction

                Deletions in strikethrough text.

For oral medicinal products that are particularly dependent on threshold concentrations for efficacy, such as contraceptives and antibiotics, patients should be advised to take those medicinal products at least 1 hour before Byetta injection.

Added the following paragraph:

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.

10.          DATE OF REVISION OF THE TEXT

                New date

6.             PHARMACEUTICAL PARTICULARS

6.4                Special precautions for storage

Changed the 'In use' storage instructions from:

In use: The pen should be returned to the refrigerator after each use.  However, chemical and physical in use stability at £25ºC has been demonstrated for 7 days (168 hours), during the 30-day in use period.

To:

In use: Store below 25°C.

10.          DATE OF REVISION OF THE TEXT

                New date

30 August 2007