Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: AstraZeneca AB, SE-151 85 Sodertalje, Sweden
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Exenatide should not be used in patients with type 1 diabetes mellitus or for the treatment of diabetic ketoacidosis.
Exenatide 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)
Immediate-release exenatide must not be administered by intravenous or intramuscular injection.
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 (see section 4.2).
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.
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.
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.
When immediate-release exenatide 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.
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.
The effect of immediate-release exenatide to slow gastric emptying may reduce the extent and rate of absorption of orally administered medicinal products. Immediate-release exenatide 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 immediate-release exenatide is given in section 4.5.
The concurrent use of immediate-release exenatide 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.
This medicinal product contains metacresol, which may cause allergic reactions.
This medicinal product contains less than 1 mmol sodium per dose, i.e. essentially “sodium-free”.
The effect of immediate-release exenatide 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 immediate-release exenatide injection. If such medicinal products are to be administered with food, patients should be advised to, if possible, take them with a meal when immediate-release exenatide 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 immediate-release exenatide injection.
Gastroresistant 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 immediate-release exenatide injection.
A delay in tmax of about 2 h was observed when digoxin, lisinopril or warfarin was administered 30 min after exenatide. No clinically relevant effects on Cmax 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 (see section 4.8).
Immediate-release exenatide 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 immediate-release exenatide injection are needed.
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; Cmax was decreased by 37%, 56%, 54% and 41%, respectively; tmax 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, Cmax and tmax 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.
Lovastatin AUC and Cmax were decreased approximately 40% and 28%, respectively, and tmax 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 (see section 5.1). Changes in LDL-C or total cholesterol_are possible, however, no predetermined dose adjustment is required. Lipid profiles should be monitored regularly.
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, Cmax or Cmin 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 Cmax of ethinyl estradiol by 45%, and Cmax of levonorgestrel by 27-41%, and a delay in tmax by 2-4 h due to delayed gastric emptying. The reduction in Cmax is of limited clinical relevance and no adjustment of dosing of oral contraceptives is required.
Interaction studies have only been performed in adults.
If a patient wishes to become pregnant, or pregnancy occurs, treatment with exenatide should be discontinued.
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.
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.
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 immediate-release exenatide is used with a sulphonylurea. Most adverse reactions associated with immediate-release exenatide were mild to moderate in intensity.
Since immediate-release exenatide has been marketed, acute pancreatitis has been reported with a frequency not known and acute renal failure has been reported uncommonly (see section 4.4).
Table 1 lists adverse reactions reported of immediate-release exenatide from clinical trials and spontaneous reports (not observed in clinical trials, frequency not known).
In clinical trials, background therapies included metformin, a sulphonylurea, a thiazolidinedione, or a combination of oral glucose-lowering medicinal products.
The reactions are listed below as MedDRA preferred term by system organ class and absolute frequency. 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).
Table 1. Adverse reactions of immediate-release exenatide identified from clinical trials and spontaneous reports:
Rare1: Anaphylactic reaction
Very common1: Hypoglycaemia (with metformin and a sulphonylurea)2, Hypoglycaemia (with a sulphonylurea)
Common1: Decreased appetite
Uncommon: Dehydration, generally associated with nausea, vomiting and/or diarrhoea
Common1: Headache2, Dizziness
Uncommon1: Dysgeusia, Somnolence
Rare1: Intestinal obstruction
Very common1: Nausea, Vomiting, Diarrhoea
Common1: Dyspepsia, Abdominal pain, Gastroesophageal reflux disease, Abdominal distension
Not known3: Acute pancreatitis (see section 4.4)
Uncommon1: Eructation
Common1: Constipation, Flatulence
Common1: Hyperhidrosis2, Pruritus, and/or urticaria
Uncommon1: Alopecia
Not known3: Macular and papular rash, Angioneurotic oedema
Uncommon1: Altered renal function, including acute renal failure, worsened chronic renal failure, renal impairment, increased serum creatinine
Common1: Feeling jittery, Asthenia2
Uncommon1: Injection site reactions
Uncommon1: Weight decreased
Not known3: International normalised ratio increased with concomitant warfarin, some reports associated with bleeding
1 Rate based on immediate-release exenatide completed long-term efficacy and safety studies n=5763 total (patients on sulphonylurea n=2971).
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 immediate-release exenatide-treated patients.
3 Spontaneous reports data (unknown denominator)
When immediate-release exenatide 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.
In studies in patients treated with immediate-release exenatide 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 immediate-release exenatide 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 immediate-release exenatide 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^ < 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 immediate-release exenatide compared to the placebo group (25% and 29% respectively). There were no episodes of major hypoglycaemia in the immediate-release exenatide arm.
In a 24-week study, where either insulin lispro protamine suspension or insulin glargine was added to existing therapy of immediate-release exenatide 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.
The most frequently reported adverse reaction was nausea. In patients treated with 5 mcg or 10 mcg immediate-release exenatide, 36% 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 immediate-release exenatide-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 immediate-release exenatide-treated patients were nausea (4% of patients) and vomiting (1%). For placebo-treated or insulin-treated patients, <1% withdrew due to nausea or vomiting.
Immediate-release exenatide-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 have been reported in approximately 5.1% of subjects receiving immediate-release exenatide in long-term (16 weeks or longer) controlled trials. These reactions have usually been mild and usually did not result in discontinuation of immediate-release exenatide.
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop anti-exenatide antibodies following treatment with immediate-release exenatide. 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 (HbA1c) 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 immediate-release exenatide in the controlled studies), had no apparent glycaemic response to immediate-release exenatide. In three insulin-comparator controlled trials (n=790) comparable efficacy and adverse events were observed in immediate-release exenatide-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).
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies this medicinal product must not be mixed with other medicinal products.
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