Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The most frequent adverse reactions were mainly gastrointestinal related (nausea which was the most frequent reaction and associated with the initiation of treatment and decreased over time, and diarrhoea).
In addition, injection site reactions (pruritus, nodules, erythema), hypoglycaemia (with a sulphonylurea), and headache occurred. Most adverse reactions associated with BYDUREON were mild to moderate in intensity.

Tabulated summary of adverse reactions
The frequency of adverse reactions of BYDUREON identified from clinical trials and spontaneous reports (not observed in clinical trials, frequency not known) are summarised in Table 1 below.

In the BYDUREON clinical trials, background therapies included diet and exercise, metformin, a sulphonylurea, a thiazolidinedione or a combination of oral glucose-lowering agents or a basal insulin.

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 (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000) and very rare (< 1/10000). and not known (cannot be estimated from the available data).

Table 1: Adverse reactions of BYDUREON identified from clinical trials and spontaneous reports 
System organ class /adverse                                    Frequency of occurrence reaction terms
Very      Common        Uncommon      Rare    Very       Not common                                          rare      known
Blood and lymphatic system disorders
4
Drug-induced thrombocytopenia                                                                        X Immune system disorders
Anaphylactic reaction                                                             X1 Metabolism and nutrition disorders
Hypoglycaemia (with a sulphonylurea)
X1
Hypoglycaemia (with insulin)                            X2,3
Decreased appetite                                      X1
Dehydration                                                            X1 Nervous system disorders
Headache                                                     X1
Dizziness                                                    X1
Dysgeusia                                                                   X1 Somnolence                                                                 X1 Gastrointestinal disorders
Intestinal obstruction                                                     X1 Acute pancreatitis (see section 4.4)                                        X1 Nausea                                          X1
Vomiting                                                     X1
1
Diarrhoea                                       X
Dyspepsia                                                    X1
Abdominal pain                                               X1
Gastroesophageal reflux disease                              X1
Abdominal distension                                         X1
Eructation                                                                  X1 Constipation                                                 X1
Flatulence                                                   X1
Skin and subcutaneous tissue disorders
Macular and papular rash                                                                                    X4 Pruritus, and/ or urticaria                                  X1
Angioneurotic oedema                                                                                        X4 Injection site abscesses and cellulitis                                                                     X4 Hyperhidrosis                                                               X1 Alopecia                                                                    X1 Renal and urinary disorders
Altered renal function, including acute renal failure, worsened chronic renal failure, renal impairment,                                            X1 increased serum creatinine (see section 4.4).
General disorders and administration site conditions
Injection site pruritus                             X1
Fatigue                                             X1
Injection site erythema                             X1
Injection site rash                                                         X1 Asthenia                                            X1
Feeling jittery                                                                         X1 Investigations
International normalised ratio
X4 increased (see section 4.4)
1 Rate based on twelve prolonged-release exenatide completed long-term efficacy and safety studies n=2868 total (patients on sulphonylurea n=1002).
2 Based on hypoglycaemic events that 1. Result in loss of consciousness, seizure, or coma which resolves after administration of glucagon or glucose OR 2. Require third-party assistance to resolve because of impairment in consciousness or behaviour and has glucose value of <54 mg/dL (3 mmol/L) OR 3. Result in symptoms consistent with hypoglycaemia with a concomitant glucose <54 mg/dL (3 mmol/L) prior to treatment.
3 Frequency reported from the 28-week controlled treatment period of the prolonged-release exenatide as add-on to insulin glargine study (N=232).
4 Rate based on prolonged-release exenatide spontaneous reports data (unknown denominator).


Description of selected adverse reactions
Drug-induced thrombocytopenia
Drug-induced thrombocytopenia (DITP) with exenatide-dependent anti-platelet antibodies has been reported in the post-marketing 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
The incidence of hypoglycaemia was increased when BYDUREON was used in combination with a sulphonylurea (24.0%versus5.4%) (see section 4.4). To reduce the risk of hypoglycaemia associated with the use of a sulphonylurea, reduction in the dose of sulphonylurea may be considered (see sections 4.2 and 4.4).

BYDUREON was associated with a significantly lower incidence of episodes of hypoglycaemia than basal insulin in patients also receiving metformin therapy (3 % versus 19 %) and in patients also receiving metformin plus sulphonylurea therapy (20 % versus 42 %).

Across 12 studies of BYDUREON most episodes (99.9% n=649) of hypoglycaemia were minor and resolved with oral administration of carbohydrate. One patient was reported with major hypoglycaemia since he had a low blood glucose value (2.2 mmol/l) and requested assistance with oral carbohydrate treatment which resolved the event.

When BYDUREON 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 adverse reaction was nausea. In patients treated with BYDUREON, generally 20 % reported at least one episode of nausea compared to 34 % of exenatide twice daily patients. Most episodes of nausea were mild to moderate. With continued therapy, the frequency decreased in most patients who initially experienced nausea.

The incidence of withdrawal due to adverse events during the 30-week controlled trial was 6 % for BYDUREON-treated patients, 5 % for exenatide twice daily -treated patients. The most common adverse events leading to withdrawal in either treatment group were nausea and vomiting. Withdrawal due to nausea or vomiting each occurred in < 1 % for BYDUREON-treated patients and 1 % for exenatide twice daily treated patients.

Injection site reactions
Injection site reactions were observed more frequently in BYDUREON-treated patients versus comparator treated patients (16 % versus range of 2-7 %) during the 6-month controlled phase of studies.
These injection site reactions were generally mild and usually did not lead to withdrawal from studies.
Patients may be treated to relieve symptoms, while continuing treatment. Subsequent injections should use a different site of injection each week. In post marketing experiences, cases with injection site abscesses and cellulitis have been reported.

Small subcutaneous injection site nodules were observed very frequently in clinical trials, consistent with the known properties of poly (D, L-lactide co-glycolide) polymer microsphere formulations. Most individual nodules were asymptomatic, did not interfere with study participation and resolved over 4 to 8 weeks.

Immunogenicity
Consistent with the potentially immunogenic properties of protein and peptide pharmaceuticals, patients may develop antibodies to exenatide following treatment with BYDUREON. In most patients who develop antibodies, antibody titres diminish over time.

The presence of antibodies (high or low titres) is not predictive of glycaemic control for an individual patient.

In clinical studies of BYDUREON, approximately 45 % of patients had low titre antibodies to exenatide at study endpoint. Overall the percentage of antibody positive patients was consistent across clinical trials.
Overall, the level of glycaemic control (HbA1c) was comparable to that observed in those without antibody titres. On average in the phase 3 studies, 12 % of the patients had higher titre antibodies. In a proportion of these the glycaemic response to BYDUREON was absent at the end of the controlled period of studies; 2.6 % of patients showed no glucose improvement with higher titre antibodies whereas 1.6 % showed no improvement while antibody negative.

Patients who developed 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 antibodies to exenatide.

For BYDUREON-treated patients, the incidence of potentially immunogenic injection site reactions (most commonly pruritus with or without erythema) during the 30-week and the two 26-week studies, was 9 %.
These reactions were less commonly observed in antibody-negative patients (4 %) compared with antibody-positive patients (13 %), with a greater incidence in those with higher titre antibodies.

Examination of antibody-positive specimens revealed no significant cross-reactivity with similar endogenous peptides (glucagon or GLP-1).

Rapid weight loss
In a 30-week study, approximately 3 % (n=4/148) of BYDUREON-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 2.6 beats per minute (bpm) from baseline (74 bpm) was observed in pooled BYDUREON clinical studies. Fifteen percent of BYDUREON 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. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il