EPERZAN Powder and solvent for solution for injection Ref.[27937] Active ingredients: Albiglutide

There is no therapeutic experience with Eperzan in patients with type 1 diabetes mellitus and it should not be used in these patients. Eperzan should not be used for treatment of diabetic ketoacidosis.

Acute pancreatitis

Use of GLP-1 receptor agonists has been associated with a risk of developing acute pancreatitis. In clinical trials, acute pancreatitis has been reported in association with Eperzan (see section 4.8).

Patients should be informed of the characteristic symptom of acute pancreatitis. If pancreatitis is suspected, Eperzan should be discontinued; if pancreatitis is confirmed, Eperzan should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

Hypoglycaemia

The risk of hypoglycaemia is increased when Eperzan is used in combination with insulin secretagogues (such as sulphonylurea) or with insulin. Therefore, patients may require a lower dose of sulphonylurea or insulin to reduce the risk of hypoglycaemia (see sections 4.2, 4.8).

Severe gastrointestinal disease

Use of GLP-1 receptor agonists may be associated with gastrointestinal adverse reactions. Eperzan has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and therefore it is not recommended in these patients.

Renal impairment

Patients with severe renal impairment receiving Eperzan experienced a higher frequency of diarrhoea, nausea, and vomiting compared to patients with mild or moderate renal impairment. These types of gastrointestinal events may lead to dehydration, and worsen renal function.

Dehydration

Dehydration, sometimes leading to renal impairment and acute renal failure, has been reported in patients treated with albiglutide and has occurred in patients without gastrointestinal side effects. Patients treated with albiglutide should be advised of the potential risk of dehydration, and take precautions to avoid fluid depletion.

Discontinuation of treatment

After discontinuation, the effect of Eperzan may continue as plasma levels of albiglutide decline slowly over about 3 to 4 weeks. Choice of other medicinal products and dose selection should be considered accordingly, as adverse reactions may continue and efficacy may, at least partly, persist until albiglutide levels decline.

Populations not studied

There is no experience in patients with NYHA class III-IV cardiac failure. Eperzan has not been studied in combination with prandial insulin, dipeptidyl peptidase-4 (DPP-4) inhibitors, or sodium/glucose cotransporter 2 (SGLT2) inhibitors.

There is limited experience of albiglutide when combined with thiazolidinediones alone, sulphonylureas + thiazolidinediones, and metformin + sulphonylureas + thiazolidinediones.

Sodium content

This medicinal product contains less than 1 mmol sodium (23 mg) per 0.5 ml dose, i.e. essentially “sodiumfree”.

Albiglutide delays gastric emptying, and has the potential to impact the absorption of concomitantly administered oral medicinal products. Albiglutide slowed gastric emptying compared with placebo for both solids and liquids when 100 mg was administered as a single dose in healthy subjects (see section 5.1). Caution should be exercised in patients receiving medicinal products with a narrow therapeutic index or medicinal products that require careful clinical monitoring.

Acarbose

Acarbose is contraindicated in patients with intestinal obstruction. Caution is advised if used concomitantly with albiglutide (see section 4.8).

Simvastatin

A single dose of simvastatin (80 mg) was administered with steady-state albiglutide (50 mg weekly). Simvastatin AUC was decreased by 40% and simvastatin C_max was increased by 18%. The AUC of simvastatin acid was increased by 36% and C_max was increased by approximately 100%. A decrease in halflife of simvastatin and simvastatin acid from ~7 hours to 3.5 hours was observed. Albiglutide showed no impact on the safety of simvastatin in clinical studies.

Digoxin

Albiglutide did not meaningfully alter the pharmacokinetics of a single-dose of digoxin (0.5 mg) when coadministered with steady-state albiglutide (50 mg weekly).

Warfarin

No clinically relevant effects on the pharmacokinetics of R- and S-enantiomers of warfarin were observed when a single dose of racemic warfarin (25 mg) was administered with steady-state albiglutide (50 mg weekly). In addition, albiglutide did not significantly alter the pharmacodynamic effects of warfarin as measured by the international normalized ratio.

Oral contraceptives

Albiglutide (50 mg weekly at steady-state) had no clinically relevant effects on the steady-state pharmacokinetics of a combination oral contraceptive containing norethindrone 0.5 mg and ethinyl estradiol 0.035 mg. In addition no clinically relevant effects on luteinizing hormone, follicle-stimulating hormone, or progesterone were observed when albiglutide and a combination oral contraceptive were co-administered.

Pregnancy

There are no or limited amount of data from the use of Eperzan in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Eperzan should not be used during pregnancy, and is not recommended in women of childbearing potential not using effective contraception.

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

Breast-feeding

There are no adequate data to support the use of Eperzan 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 (see section 5.3).

Fertility

There are no data on the effects of Eperzan on human fertility. Studies in mice showed reduced oestrous cycling at maternally toxic doses, but did not indicate harmful effects with respect to fertility (see section 5.3). The potential risk for humans is unknown.

Eperzan has no or negligible influence on the ability to drive or use machines. When Eperzan 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 (see section 4.4).

Summary of the safety profile

Over 2,300 patients have received Eperzan 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 Eperzan, 30 mg or 50 mg weekly subcutaneously.

The most serious adverse reaction in clinical trials was acute pancreatitis (see section 4.4).

The most frequent adverse reactions during clinical trials which occurred in 5% of patients receiving Eperzan 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 Eperzan 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 Table 1.

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.

Table 1. 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 Eperzan 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 Eperzan 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 Eperzan 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 Eperzan compared to 7% with all comparators and led to discontinuation in 2% of all patients treated with Eperzan. 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 Eperzan 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 Eperzan was used as monotherapy, the incidence of symptomatic hypoglycaemia (<3.9 mmol/l) was similar for Eperzan 30 mg (2%), Eperzan 50 mg (1%) and placebo (3%).

The rate of symptomatic hypoglycaemia was higher for Eperzan 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 Eperzan compared to 0.8% of patients in the all comparators group. For Eperzan, 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 Eperzan and 0.5% of patients in the all comparators group. In both the Eperzan 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 Eperzan 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 Eperzan were reactions at the injection site and GI related events, each <2%.

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 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.