Eli Lilly and Company Limited

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