Exenatide

In patients with end-stage renal disease receiving dialysis, single doses ofimmediate-release exenatide 5 mcg increased frequency and severity of gastrointestinal adverse reactions. Exenatide 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.

There have been uncommon, 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 medicinal products known to affect renal function/hydration status. Concomitant medicinal products 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 medicinal products, including exenatide.

Lovastatin AUC and C_max were decreased approximately 40% and 28%, respectively, and t_max was delayed about 4 h when immediate-release exenatide (10 mcg 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 immediate-release exenatide and HMG CoA reductase inhibitors was not associated with consistent changes in lipid profiles. Changes in LDL-C or total cholesterol_are possible, however, no predetermined dose adjustment is required. Lipid profiles should be monitored regularly.

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 spontaneously during concomitant use of warfarin and exenatide. INR should be closely monitored during initiation and dose increase of immediate-release exenatide therapy in patients on warfarin and/or cumarol derivatives.

Administration of a combination oral contraceptive (30 mcg ethinyl estradiol plus 150 mcg levonorgestrel) one hour before immediate-release exenatide (10 mcg BID) did not alter the AUC, C_max or C_min of either ethinyl estradiol or levonorgestrel. Administration of the oral contraceptive 30 minutes after immediate-release exenatide did not affect AUC but resulted in a reduction of the C_max of ethinyl estradiol 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.

Paracetamol was used as a model medicinal product to evaluate the effect of exenatide on gastric emptying. When 1000 mg paracetamol was given with 10 mcg immediate-release exenatide (0 h) and 1 h, 2 h and 4 h after immediate-release exenatide 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 immediate-release exenatide injection. No adjustment to paracetamol dosing is required based on these study results.

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 severe gastrointestinal disease.

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 exenatide. Resolution of pancreatitis has been observed with supportive treatment but very rare cases of necrotising or hemorrhagic pancreatitis and/or death have been reported. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, exenatide should be discontinued; if acute pancreatitis is confirmed, exenatide should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

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. Patients with rapid weight loss should be monitored for signs and symptoms of cholelithiasis.

There are no adequate data from the use of exenatide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Exenatide should 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 if breast-feeding.

Women of childbearing potential

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

Fertility

No fertility studies in humans have been conducted.

Exenatide has minor influence on the ability to drive and use machines. When exenatide 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.