Special Warning : אזהרת שימוש

4.4     Special warnings and precautions for use
BYDUREON should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.

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

BYDUREON must not be administered by intravenous or intramuscular injection.

Renal impairment
In patients with end-stage renal disease receiving dialysis, single doses of exenatide twice daily increased frequency and severity of gastrointestinal adverse reactions therefore BYDUREON is not recommended for use in patients with end-stage renal disease or severe renal impairment (creatinine clearance < 30 ml/min). Use BYDUREON with caution in patients with moderate renal impairment (creatinine clearance 30-50 mL/min).

There have been uncommon events of altered renal function with exenatide, 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 agents, including exenatide.
Severe gastrointestinal disease
BYDUREON 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 BYDUREON is not recommended in patients with severe gastrointestinal disease.

Acute pancreatitis
Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis.
. There have been spontaneously reported events of acute pancreatitis with BYDUREON. Resolution of pancreatitis has been observed with supportive treatment, but very rare cases of necrotising or haemorrhagic pancreatitis and/or death have been reported. 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, BYDUREON should be discontinued; if acute pancreatitis is confirmed, BYDUREON should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Drug-Induced Thrombocytopenia
Serious bleeding, which may be fatal, from drug-induced immune-mediated thrombocytopenia has been reported in the post-marketing setting with exenatide use. Drug-induced thrombocytopenia is an immune- mediated reaction, with exenatide-dependent anti-platelet antibodies. In the presence of exenatide, these antibodies cause platelet destruction. If drug-induced thrombocytopenia is suspected, discontinue BYDUREON immediately and do not re-expose the patient to exenatide. Upon discontinuation, thrombocytopenia can persist due to the prolonged exenatide exposure from BYDUREON (about 10 weeks).


Concomitant medicinal products
The concurrent use of BYDUREON with insulin, D-phenylalanine derivatives (meglitinides), alpha-glucosidase inhibitors, dipeptidyl peptidase-4 inhibitors or other GLP-1 receptor agonists has not been studied. The concurrent use of BYDUREON and exenatide twice daily (BYETTA) has not been studied and is not recommended.

Interaction with warfarin
There have been spontaneously reported cases of increased INR (International Normalized Ratio), sometimes associated with bleeding, with concomitant use of warfarin and exenatide (see section 4.5).

Hypoglycaemia
The risk of hypoglycaemia was increased when BYDUREON was used in combination with a sulphonylurea in clinical trials. Furthermore, 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.

Rapid weight loss
Rapid weight loss at a rate of >1.5 kg per week has been reported in patients treated with exenatide.
Weight loss of this rate may have harmful consequences. Patients with rapid weight loss should be monitored for signs and symptoms of cholelithiasis.

Discontinuation of treatment
After discontinuation, the effect of BYDUREON may continue as plasma levels of exenatide decline over 10 weeks. Choice of other medicinal products and dose selection should be considered accordingly, as adverse reactions may continue, and efficacy may, at least partly, persist until exenatide levels decline.

Excipients
Sodium content: This medicine contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially “sodium-free”.

Effects on Driving

4.7   Effects on ability to drive and use machines
BYDUREON has minor influence on the ability to drive and use machines. When BYDUREON is used in combination with a sulphonylurea, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines.