Bydureon BCise Adverse Reactions

Summary of the safety profile: The most frequent adverse reactions during the clinical studies were gastrointestinal-related (mainly nausea (8 %), which tended to dissipate with continued treatment), headache (4 %) and injection site reactions, such as injection site pruritus (3 %) and injection site erythema (2 %). In addition, hypoglycaemia with a sulphonylurea occurred very commonly (see Description of selected adverse reactions, as follows). Most adverse reactions were mild to moderate in intensity.
Tabulated list of adverse reactions: The frequency of adverse reactions of Bydureon BCise identified from clinical studies are summarised in Table 8 as follows.
The pooled clinical studies data set for Bydureon BCise comprises two phase 3 comparator-controlled studies of 6 to 12 months duration. The follow-up and extension phases of studies are included in the pool. Background therapies included diet and exercise alone or with metformin, a sulphonylurea, a thiazolidinedione or a combination of oral glucose-lowering medicinal products. Adverse reactions that have been observed with the prolonged-release exenatide but not in clinical studies with Bydureon BCise are also included in Table 8.
Background therapies in the prolonged-release exenatide clinical trials included diet and exercise, metformin, a sulphonylurea, a thiazolidinedione, a combination of oral glucose-lowering agents or a basal insulin.
The reactions are listed as follows 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). (See Table 8.)

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Description of selected adverse reactions: Drug-induced thrombocytopenia: Drug-induced thrombocytopenia (DITP) with exenatide-dependent anti-platelet antibodies has been reported in the postmarketing setting. DITP is an immune-mediated reaction that is caused by drug-dependent platelet-reactive antibodies. These antibodies cause destruction of platelets in the presence of the sensitizing drug.
Hypoglycaemia: There were no events of major hypoglycaemia with Bydureon BCise. The overall incidence of minor hypoglycaemia was 6.3 %. This incidence was increased when it was used in combination with a sulphonylurea (26.1 %) compared to no sulphonylurea (0.9 %) (see Precautions). To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea may be considered (see Dosage & Administration and Precautions).
When prolonged-release exenatide was added to basal insulin, no initial dose adjustment of insulin was required. Prolonged-release exenatide in combination with basal insulin showed no clinically significant differences in the incidence of hypoglycaemic episodes compared to insulin. There were no episodes of major hypoglycaemia in the prolonged-release exenatide with insulin group.
Nausea: The most frequently reported gastrointestinal adverse reaction was nausea. During the controlled period of the clinical study comparing Bydureon BCise with immediate-release exenatide, nausea was reported in 9.6 % and 20.5 % of patients in each group. Overall, 9.3 % of patients treated with Bydureon BCise reported nausea during the controlled period of both clinical studies. Most episodes of nausea were mild to moderate, associated with the initiation of treatment and decreased over time.
Injection site reactions: During the controlled period of the clinical studies, injection site reactions were observed more frequently in patients treated with Bydureon BCise versus comparator-treated patients (24 % versus 4 % with immediate-release exenatide). These injection site reactions were generally mild and usually did not lead to discontinuation of study medication. Patients may be treated to relieve symptoms, while continuing treatment. Subsequent injections should use a different site of injection each week. In postmarketing experience with prolonged-release exenatide, cases with injection site abscesses and cellulitis have been reported.
Subcutaneous injection site nodules were observed frequently in clinical studies, consistent with the known properties of poly (D,L-lactide co-glycolide) polymer microsphere formulations. Most individual nodules did not interfere with study participation and resolved over time.
Immunogenicity: Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop antibodies to exenatide following treatment with prolonged-release exenatide.
Approximately 42 % of patients developed low titre antibodies to exenatide and 32 % of patients developed high titre antibodies at any time during the studies. The percentage of these subjects with positive antibody titres, in particular high titres, peaked at approximately weeks 8 to 16 of dosing and then diminished over time. At the study endpoint, approximately 43 % of patients had low titre antibodies to exenatide and 14 % of patients had high titre antibodies. Overall, the level of glycaemic control (HbA_1c) in patients treated with Bydureon BCise with low titre antibodies at the last visit (-1.1 % to -1.5 %) was comparable to that observed in those without antibody titres (-1.1 % to -1.4 %). While patients with high titre antibodies at the last visit had an attenuated HbA_1c response, HbA_1c reductions in these patients were clinically relevant (-0.6 % to -0.7 %).
Amongst patients treated with Bydureon BCise evaluable for antibodies (N = 393), the incidence of potentially immunogenic injection site reactions (most commonly injection site nodule) during the two studies was approximately 20 %. These reactions were less commonly observed in antibody-negative patients (16 %) and patients with low titre antibodies (16 %) compared with those with high titre antibodies (27 %).
Rapid weight loss: In a 30-week study, approximately 3 % (n = 4/148) of prolonged-release exenatide treated patients experienced at least one-time period of rapid weight loss (recorded body weight loss between two consecutive study visits of greater than 1.5 kg/week).
Increased heart rate: A mean increase in heart rate (HR) of 2.4 beats per minute (bpm) from baseline (74 bpm) was observed in the controlled period of the Bydureon BCise clinical studies. Fifteen percent of prolonged-release exenatide treated patients had mean increases in HR of ≥10 bpm; approximately 5 % to 10 % of subjects within the other treatment groups had mean increases in HR of ≥10 bpm.
Reporting of suspected adverse reactions: 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 to AstraZeneca.