Albiglutide

There are no or limited amount of data from the use of albiglutide in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Albiglutide should not be used during pregnancy, and is not recommended in women of childbearing potential not using effective contraception.

Albiglutide should be discontinued at least 1 month before a planned pregnancy due to the long washout period for albiglutide.

There are no adequate data to support the use of albiglutide during breast-feeding in humans. It is not known if albiglutide is excreted in human milk. Given that albiglutide is an albumin-based protein therapeutic agent, it is likely to be present in human milk. A decision should be made whether to discontinue breast-feeding or to discontinue therapy, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the mother. Decreased body weight in offspring was observed in mice treated with albiglutide during gestation and lactation.

Fertility

There are no data on the effects of albiglutide on human fertility. Studies in mice showed reduced oestrous cycling at maternally toxic doses, but did not indicate harmful effects with respect to fertility. The potential risk for humans is unknown.

Albiglutide has no or negligible influence on the ability to drive or use machines. When albiglutide is used in combination with insulin secretagogues (such as sulphonylureas) or insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines.

Summary of the safety profile

Over 2,300 patients have received albiglutide in 8 placebo- or active-controlled phase III studies.

Background therapies in these studies included diet and exercise, metformin, sulphonylurea, thiazolidinedione, insulin glargine, or a combination of antidiabetic medicinal products.

The duration of studies ranged from 32 weeks to up to 3 years. Frequency categories below reflect combined data for the 2 doses of albiglutide, 30 mg or 50 mg weekly subcutaneously.

The most serious adverse reaction in clinical trials was acute pancreatitis.

The most frequent adverse reactions during clinical trials which occurred in 5% of patients receiving albiglutide were diarrhoea, nausea, and injection site reactions including rash, erythema, or itching at the injection site.

Tabulated summary of adverse reactions

The table presents the adverse reactions that occurred more frequently among patients treated with albiglutide than patients treated with all comparators. Adverse reactions reported from a pooled analysis of seven placebo- and active-controlled phase III studies over the entire treatment period are presented in the table below.

Patient 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions from phase III studies during the entire treatment periods and postmarketing reports:

Description of selected adverse reactions

Allergic reactions

Possible hypersensitivity reactions including angioedema, erythema, generalised pruritus and rash with dyspnoea, have been reported with albiglutide.

Pancreatitis

The incidence of pancreatitis (adjudicated as likely to be related to therapy) in the clinical studies was 0.3% for albiglutide compared to 0% for placebo and 0.1% for comparators (i.e. liraglutide, pioglitazone, glimepiride, sitagliptin, and insulin glargine) with or without additional background antidiabetic therapy (e.g. metformin).

Gastrointestinal events

Gastrointestinal events occurred with a higher frequency for albiglutide compared to all comparators (38% versus 32%). Diarrhoea (13% versus 9%), nausea (12% versus 11%), vomiting (5% versus 4%), and constipation (5% versus 4%) were the most frequently reported, and the majority of events occurred within the first 6 months.

Gastrointestinal events with albiglutide occurred more frequently in patients with moderate to severe renal impairment (eGFR 15 to 59 ml/min/1.73 m²) than in those with mild renal impairment or normal renal function.

Injection site reactions

Injection site reactions (typically including rash, erythema, or itching at the injection site) occurred in 15% of patients treated with albiglutide compared to 7% with all comparators and led to discontinuation in 2% of all patients treated with albiglutide. Generally, injection site reactions were mild in intensity and did not require treatment.

Immunogenicity

The percentage of patients who developed antibodies to albiglutide on treatment was 4% (137/3,267). None of these antibodies were shown to neutralise the activity of albiglutide in an in vitro assay and antibody formation was generally transient and was not associated with reduced efficacy (HbA1c and FPG). Although most patients with injection site reactions were antibody negative (~85%), injection site reactions were reported more frequently for antibody positive (41%, N = 116) than antibody negative patients (14%, N = 1,927). These events were predominately mild and did not lead to discontinuation. Otherwise, the pattern of adverse events was generally similar for antibody positive and negative patients.

Hypoglycaemia

Severe hypoglycaemia requiring the assistance of another person for treatment occurred uncommonly: 0.3% among patients receiving albiglutide and 0.4% among patients receiving a comparator. Most patients with severe hypoglycaemic events in clinical studies were receiving concurrent sulphonylurea or insulin and none required hospitalisation or led to withdrawal of treatment.

When albiglutide was used as monotherapy, the incidence of symptomatic hypoglycaemia (<3.9 mmol/l) was similar for albiglutide 30 mg (2%), albiglutide 50 mg (1%) and placebo (3%).

The rate of symptomatic hypoglycaemia was higher for albiglutide when used in combination with a sulphonylurea (15% to 22%) or with insulin (18%) compared to combinations not including a sulphonylurea or insulin (1% to 4%). Among patients randomised to other comparators, the incidence of symptomatic hypoglycaemia was 7% to 33% when used with a sulphonylurea or insulin and 2% to 4% in combinations without these medicinal products.

Pneumonia

Pneumonia occurred in 2% of patients receiving albiglutide compared to 0.8% of patients in the all comparators group. For albiglutide, these were single episodes of pneumonia in patients participating in studies with 32 weeks up to 3 years of observation.

Atrial fibrillation / flutter

Atrial fibrillation/flutter occurred in 1% of patients receiving albiglutide and 0.5% of patients in the all comparators group. In both the albiglutide and all comparator groups, patients with events were generally male, older, or had renal impairment.

Heart rate

In the Phase III studies in type 2 diabetes patients, small increases in heart rate (1 to 2 bpm) were observed with albiglutide. In a thorough QT study in healthy subjects, an increase in heart rate (6 to 8 bpm) was observed after repeat dosing with albiglutide 50 mg compared to baseline values.

Withdrawals

In clinical trials of at least 2 years duration, 8% of subjects in the albiglutide group discontinued active treatment because of an adverse event compared with 6% in the all comparators group. The most common events leading to discontinuation of albiglutide were reactions at the injection site and GI related events, each <2%.