Eperzan - summary of medicine characteristics

1. NAME OF THE MEDICINAL PRODUCT

Eperzan 30 mg powder and solvent for solution for injection

Eperzan 50 mg powder and solvent for solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Eperzan 30 mg powder and solvent for solution for injection

Each pen delivers 30 mg albiglutide per 0.5 ml dose following reconstitution.

Eperzan 50 mg powder and solvent for solution for injection

Each pen delivers 50 mg albiglutide per 0.5 ml dose following reconstitution.

Albiglutide is a recombinant fusion protein consisting of two copies of a 30-amino acid sequence of modified human glucagon-like peptide 1 genetically fused in series to human albumin.

Albiglutide is produced in Saccharomyces cerevisiae cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Powder and solvent for solution for injection.

Powder: lyophilised white to yellow powder.

Solvent: A clear, colourless solution.

4. CLINICAL PARTICULARS4.1 Therapeutic indications

Eperzan is indicated for the treatment of type 2 diabetes mellitus in adults to improve glycaemic control as:

Monotherapy

When diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to contraindications or intolerance.

Add-on combination therapy

In combination with other glucose-lowering medicinal products including basal insulin, when these, together with diet and exercise, do not provide adequate glycaemic control (see section 4.4 and 5.1 for available data on different combinations).

4.2 Posology and method of administration

Posology

The recommended dose of Eperzan is 30 mg once weekly, administered subcutaneously.

The dose may be increased to 50 mg once weekly based on individual glycaemic response.

When Eperzan is added to existing metformin therapy, the current metformin dose can be continued unchanged. It may be necessary to reduce the dose of concomitantly administered insulin secretagogues (such as sulphonylureas) or insulin to reduce the risk of hypoglycaemia when starting Eperzan (see sections 4.4 and 4.8).

The use of Eperzan does not require specific blood glucose self-monitoring. However, when used in combination with a sulphonylurea or a basal insulin, blood glucose self-monitoring may become necessary to adjust the dose of the sulphonylurea or the basal insulin.

Eperzan may be administered at any time of day without regard to meals.

Eperzan should be administered once a week on the same day each week. The day of weekly administration can be changed if necessary as long as the last dose was administered 4 or more days previously.

If a dose is missed, it should be administered as soon as possible within 3 days after the missed dose. Thereafter, patients can resume dosing on their usual day of administration. If it is more than 3 days after the missed dose, patients should wait and administer their next regularly scheduled weekly dose.

Elderly patients (>65 years)

No dose adjustment is required based on age. The clinical experience in patients >75 years is very limited (see section 5.2).

Patients with renal impairment

No dose adjustment is necessary for patients with mild and moderate renal impairment (eGFR 60 to 89 and 30 to 59 ml/min/1.73m2, respectively) (see sections 4.4, 4.8, 5.1, 5.2). Experience in patients with severe renal impairment (<30 ml/min/1.73m2) or on dialysis is very limited and therefore Eperzan is not recommended in this population (see sections 4.4, 4.8, 5.1, 5.2).

Patients with hepatic impairment

No dose adjustment is recommended for patients with hepatic impairment. There have been no studies in patients with hepatic impairment (see section 5.2).

Paediatric population

The safety and efficacy of Eperzan in children and adolescents under 18 years have not been established (see section 5.2). No data are available.

Method of administration

Eperzan is intended for patient self-administration as a subcutaneous injection in the abdomen, thigh or upper arm region.

It must not be administered intravenously or intramuscularly.

Each pen injector should be used by one person only and is for single use.

The lyophilised powder contained within the pen must be reconstituted prior to administration.

For full instructions on the reconstitution and administration of Eperzan see section 6.6 and the instructions for use included in the package leaflet.

When using Eperzan with insulin, each medicinal product must be administered as a separate injection. The two medicinal products should never be mixed. It is acceptable to inject Eperzan and insulin in the same body region but the injections should not be adjacent to each other.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4 Special warnings and precautions for use

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 “sodium-free”.

4.5 Interaction with other medicinal products and other forms of interaction

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 Cmax was inc:eased by 18%. The AUC of simvastatin acid was increased by 36% and Cmax 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.

4.6 Fertility, pregnancy and lactation

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.

4.7 Effects on ability to drive and use machines

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).

4.8 Undesirable effects

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

System organ class	Very common	Common	Uncommon	Rare	Not known
Infections and infestations		Pneumonia
Immune system disorders				Hypersensitivity reaction
Metabolism and nutrition disorders	Hypoglycaemia (when Eperzan is used in combination with insulin or sulphonylurea)	Hypoglycaemia (when Eperzan is used as monotherapy or in combination with metformin or pioglitazone)			Decreased appetite
Cardiac disorders		Atrial fibrillation/flutt er
Gastrointestinal disorders	Diarrhoea, nausea	Vomiting, constipation, dyspepsia, gastrooesophag eal reflux disease	Pancreatitis, intestinal obstruction 9	>
General disorders and administration site conditions	Injection site reactions

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/tlut­ter 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.

4.9 Overdose

During clinical studies of patients with type 2 diabetes, the highest dose of Eperzan administered was 100 mg subcutaneously every four weeks for 12 weeks. This dose was associated with an increased frequency of nausea, vomiting, and headache.

There is no specific antidote for overdose with Eperzan. In the event of a suspected overdose, the appropriate supportive clinical care should be instituted, as dictated by the subject’s clinical status. Anticipated symptoms of an overdose may be severe nausea, vomiting or headache. A prolonged period of observation and treatment for these symptoms may be necessary, taking into account the half-life of albiglutide (5 days).

5. PHARMACOLOGICAL PROPERTIES5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in diabetes. Other blood glucose lowering drugs excl. insulins. Glucagon-like peptide-1 (GLP-1) analogues. ATC code: A10BJ04

Mechanism of action

Albiglutide is an agonist of the GLP-1 receptor and augments glucose-dependent insulin secretion.

Albiglutide also slows gastric emptying.

Pharmacodynamic effects

Glucose control

Eperzan lowers fasting glucose and reduces postprandial glucose excursions. The majority of the observed reduction in fasting plasma glucose occurs after a single dose, consistent with the pharmacokinetic profile of albiglutide.

In patients with type 2 diabetes who received 2 doses of albiglutide 32 mg (Day 1 and 8), a statistically significant reduction (24%) in postprandial glucose AUQ0.5.4.5 h) was observed compared to placebo following a standardised breakfast meal on Day 9.

A single dose of albiglutide 50 mg did not impair the glucagon, epinephrine, norepinephrine, cortisol or growth hormone counter-regulatory hormone response to hypoglycaemia.

Gastric motility

Albiglutide slowed gastric emptying compared with placebo for both solids and liquids when 100 mg was administered as a single dose in healthy subjects. For solids, gastric emptying t1/2 increased from 1.14 h to 2.23 h (p=0.0112). For liquids, gastric emptying t1/2 increased from 0.28 h to 0.69 h (p=0.0018).

Clinical efficacy and safety

A total of 2,365 patients with type 2 diabetes were treated with Eperzan and 2,530 received other study medications in 8 active and placebo-controlled phase III clinical trials. Studies evaluated the use of Eperzan 30 mg and 50 mg once weekly, allowing for optional titration of Eperzan from 30 mg to 50 mg once weekly in 5 of the 8 studies. Across the 8 clinical trials, and including subjects in all treatment groups, a total of 19% of patients (N = 937) were 65 years of age and older, and 2% (N = 112) were 75 years of age and older, 52% were male, with a mean body mass index (BMI) of 33 kg/m2. Sixty seven percent of patients were Caucasian, 15% African American/African heritage and 11% Asian; 26% of patients were Hispanic/Latino.

No overall differences in glycaemic effectiveness or body weight were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes).

Monotherapy

The efficacy of Eperzan was evaluated in a 3-year randomised, double-blind, placebo-controlled, multicentre study (n = 296) in patients inadequately controlled on diet and exercise. Patients were randomised (1:1:1) to Eperzan 30 mg once weekly, Eperzan 30 mg once weekly uptitrated to 50 mg once weekly at week 12, or placebo. The primary endpoint was change in HbA1c from baseline at 52 weeks. Compared to placebo, treatment with Eperzan 30 mg and 50 mg SC weekly resulted in statistically significant reductions in HbA1c from baseline at Week 52. The change from baseline in HbA1c at the 6 month timepoint was also statistically significant for the 30 mg (0.9%) and 50 mg (1.1%) weekly doses of Eperzan (see Table 2).

Table 2. Results at 52 weeks in a placebo-controlled study with two doses of Eperzan (30 vs. 50 mg SC weekly) as monotherapy

	Eperzan 30 mg weekly	Eperzan 50 mg weekly	Placebo
ITTa (N)	N = 100	N = 97	N = 99
HbA1c (%)
Baseline (mean) Change at Week 52b Difference from placebob (95% CI)	8.05 –0.70 –0.8 (-1.1, –0.6)c	8.21 –0.9 –1.0 (-1.3, –0.8) c	8.02 +0.2
Patients (%) Achieving HbA1c <7%	49	40	21
Body Weight (kg)
Baseline (mean) Change at Week 52b Difference from placebob (95% CI)	96 –0.4 0.3 (-0.9, 1.5)	97 –0.9 –0.2 (-1.4, 1.0)	96 –0.7

Intent to treat population – last observation carried forward

Adjusted mean

P<0.05 for treatment difference

a

b

c

Add-on to metformin

The efficacy of Eperzan was evaluated in a 3-year, randomised, double-blind, multicentre study (n = 999). On background therapy of metformin >1,500 mg daily, Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly afte" a minimum of 4 weeks) was compared to sitagliptin 100 mg daily, glimepiride 2 mg daily (with optional titration to 4 mg daily), or placebo. The primary endpoint was change in HbA1c from baseline at 2 years compared to placebo. Results at 104 weeks are presented in Table 3. Eperzan demonstrated glycaemic lowering and was statistically superior in reduction in HbA1c from baseline compared to placebo, sitagliptin, or glimepiride (see Table 3).

Table 3. Results at 104 weeks in a placebo-controlled study comparing Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) to sitagliptin 100 mg daily and glimepiride 2 to 4 mg daily as add-on therapy in patients inadequately controlled on metformin >1,500 mg daily

	Eperzan 30 mg/50 mg Weekly + Metformin > 1,500 mg daily	Placebo + Metformin > 1,500 mg daily	Sitagliptin 100 mg daily + Metformin > 1,500 mg daily	Glimepiride 2 to 4 mg daily + Metformin > 1,500 mgd aily
ITT a (N)	297	100	300	302
HbAic (%)
Baseline (mean) Change at Week 104b Difference from placebo + metforminb, (95% CI) Difference from sitagliptin + metforminb, (95% CI) Difference from glimepiride + metforminb, (95% CI)	8.1 –0.6 –0.9 (-1.2, –0.7)c –0.4 (-0.5, –0.2)c –0.3 (-0.5, –0.1)c	8.1 +0.3	8.1 –0.3	8.1 –0.4
Proportion Achieving HbA1c <7%	39	16	32	31
Body Weight (kg)
Baseline (mean) Change at Week 104 b Difference from placebo + metforminb, (95% CI) Difference from sitagliptin + metforminb , (95% CI) Difference from glimepiride + metforminb , (95% CI)	90 –1.2 –0.2 (-1.1, 0.7) –0.4 (-1.0, 0.3) –2.4 (-3.0, –1.7)c	92 –1.0	90 –0.9	92 +1.2

a Intent to treat population – last observatio n carried forward

b Adjusted mean

c P<0.05 for treatment difference

Add-on to pioglitazone

The efficacy of Eperzan was evaluated in a 3-year, randomised, double-blind, multicentre study (n = 299).

Eperzan 30 mg SC weekly was compared to placebo in patients inadequately controlled on pioglitazone >30 mg daily (with or without metformin >1,500 mg daily).

Compared to placebo, treatment with Eperzan resulted in statistically significant reductions from baseline in HbAic (-0.8% for Eperzan versus –0.1% for placebo, p<0.05) and FPG (-1.3 mmol/l for Eperzan versus +0.4 mmol/l for placebo, p<0.05) at 52 weeks. The change from baseline in weight did not differ significantly between treatment groups (see Table 4).

Table 4. Results at 52 weeks in a placebo-controlled study comparing Eperzan 30 mg SC weekly as add-on therapy in patients inadequately controlled on pioglitazone >30 mg daily ± metformin >1,500 mg daily

	Eperzan 30 mg Weekly + Pioglitazone > 30 mg daily (+/- Metformin > 1,500 mg daily)	Placebo + Pioglitazone > 30 mg daily (+/- Metformin > 1,500 mg daily)
ITT a (N)	N = 150	N = 149
HbAic (%)
Baseline (mean) Change at Week 52b Difference from placebo + pioglitazoneb (95% CI)	8.1 –0.8 –0.8 (-1.0, –0.6) c	8.1 –0.05
Proportion Achieving HbA1c <7%	44	15
Body Weight (kg)
Baseline (mean) Change at Week 52b Difference from placebo + pioglitazoneb (95% CI)	98 0.3 –0.2 (-1.2, 0.8)	100 +0.5

a Intent to treat population – last observation carried forward

b Adjusted mean

c P<0.05 for treatment difference

Add-on to metformin plus sulphonylurea

The efficacy of Eperzan was evaluated in a 3-year, randomised, double-blind, multicentre study (n = 657). On background therapy of metformin >1,500 mg daily plus glimepiride 4 mg daily, Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly after a minimum of 4 weeks) was compared to placebo or pioglitazone 30 mg daily (with optional titration to 45 mg/day). The primary endpoint was change in HbAic from baseline at 52 weeks compared to placebo. At 52 weeks, treatment with Eperzan resulted in statistically significant reductions from baseline in HbAic compared to placebo. Treatment with Eperzan did not meet the pre-specified noninferiority margin (0.3%) against pioglitazone for HbAic. The change from baseline in weight for Eperzan did not differ significantly from placebo but was significantly less compared to pioglitazone (see Table 5).

Table 5. Results at 52 weeks in a placebo-controlled study comparing Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) to pioglitazone 30 mg daily (with optional titration to 45 mg/day) as add-on therapy in patients inadequately controlled on metformin + sulphonylurea (glimepiride 4 mg daily)

	Eperzan 30 mg/50 mg Weekly + Metformin > 1,500 mg daily + Glimepiride 4 mg daily	Placebo + Metformin > 1,500 mg daily + Glimepiride 4 mg daily	Pioglitazone + Metformin > 1,500 mg daily + Glimepiride 4 mg daily
ITT a (N)	269	115	273
HbA 1c (%)
Baseline (mean) Change at Week 52b Difference from placebo + met + glimb (95% CI) Difference from pioglitazone + met + glimb (95% CI)	8.2 –0.6 –0.9 (-1.1, –0.7)c 0.3 (0.1, 0.4)	8.3 +0.33	8.3 –0.80
Proportion Achieving HbAic <7%	30	9	35
Body Weight (kg)
Baseline (mean) Change at Week 52b Difference from placebo + met + glimb (95% CI) Difference from pioglitazone + met + glimb (95% CI)	91 –0.4 –0.03 (-0.9, 0.8) –4.9 (-5.5, –4.2)c	90 –0.4	91 +4.4

a Intent to treat population – last observation carried forward b Adjusted mean

c P<0.05 for treatment difference

Add-on to insulin glargine

The efficacy of Eperzan was evaluated in a 52 week, randomised, open-label, multicentre noninferiority study (n = 563). On background therapy of insulin glargine (started at 10 units and titrated to > 20 units per day), Eperzan 30 mg SC once weekly (with uptitration to 50 mg if inadequately controlled after Week 8) was compared to prandial insulin lispro (administered daily at mealtimes, started according to standard of care and titrated to effect). The primary endpoint was change in HbAic from baseline at 26 weeks. At Week 26, the mean daily dose of insulin glargine was 53 IU for Eperzan and 51 IU for lispro. The mean daily dose of insulin lispro at Week 26 was 31 IU, and at Week 52, 69% of patients treated with Eperzan were on 50 mg weekly. At 26 weeks, the between-treatment difference in HbAic of 0.2% for Eperzan and insulin lispro met the pre-specified noninferiority margin (0.4%). Treatment with Eperzan resulted in a mean weight loss for Eperzan (-0.7 kg) compared to a mean weight gain for insulin lispro (+0.8 kg) and the difference between treatment groups was statistically significant (see Table 6).

Table 6. Results at 26 weeks in a study comparing Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) to prandial insulin lispro as add-on therapy in patients inadequately controlled on insulin glargine alone

	Eperzan + Insulin glargine ( > 20 units per day)	Insulin lispro + Insulin glargine ( > 20 units per day)
ITT a(N)	N = 282	N = 281
HbA1c (%)
Baseline (mean) Change at Week 26b Difference from lispro insulinb (95% CI) P value (noninferiority)	8.47 –0.8 –0.2 (-0.3, 0.0) <0.0001	8.43 –0.6
Proportion Achieving HbA1c <7%	30%	25%
Body Weight (kg)
Baseline (mean) Change at Week 26b Difference from lispro insulinb (95% CI)	93 –0.7 –1.5 (-2.1, –1.0) c	92 +0.8

a Intent to treat population – last observatio n carried forward

b Adjusted mean

c P<0.05 for treatment difference

In patients who completed the study (52 weeks), the adjusted mean change in baseline in HbA1c was –1.0% for Eperzan (N = 121) and –0.9% for insulin lispro (N = 141). The adjusted mean change in body weight from baseline at 52 weeks was –1.0 kg for Eperzan (N = 122) and +1.7 kg for insulin lispro (N = 141). These data exclude the use of antidiabetic therapies permitted after the efficacy assessment if glycaemic thresholds were exceeded.

Active-controlied study versus insulin glargine as add-on to metformin ± sulphonylurea

The efficacy of Eperzan was evaluated in a 3-year, randomised (2:1), open-label, insulin glargine-controlled noninfei;ority study (n = 735). On background therapy of metformin >1,500 mg daily (with or without sulphonylurea), Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) was compared to insulin glargine (started at 10 units and titrated weekly per prescribing information). The primary endpoint was change in HbA1c from baseline at 52 weeks. The starting total daily dose of insulin glargine ranged between 2 and 40 units (median daily dose of 10 units) and ranged between 3 and 230 units (median daily dose of 30 units) at Week 52. The median daily dose of insulin glargine used prior to hyperglycaemic rescue was 10 units (range 2 to 40 units) at study start and 30 units (range 3 to 230 units) at Week 52. At Week 156, 77% of patients treated with Eperzan were uptitrated to 50 mg SC weekly. The between-treatment difference in HbA1c of 0.1% (-0.04, 0.27) from baseline at 52 weeks for Eperzan and insulin glargine met the prespecified noninferiority margin (0.3%). A statistically significant decrease in body weight was observed for Eperzan compared to an increase in body weight for insulin glargine and the difference in weight change was statistically significant (see Table 7).

Table 7. Results at 52 weeks in an active-controlled study comparing Eperzan 30 mg SC weekly (with optional uptitration to 50 mg weekly) to insulin glargine (titrated weekly per prescribing information) as addon therapy in patients inadequately controlled on metformin ± sulfonylurea

	Eperzan 30 mg/50 mg Weekly ± Metformin (with or without sulphonylurea)	Insulin glargine ± Metformin (with or without sulphonylurea)
ITT a (N)	496	239
HbAic (%)
Baseline (mean) Change at Week 52b Difference from insulin glargineb (95% CI) P value (noninferiority)	8.28 –0.7 0.1 (-0.04, 0.3) <0.0086	8.36 –0.8
Proportion Achieving HbA1c <7%	32	33
Body Weight (kg)
Baseline (mean) Change at Week 52b Difference from insulin glargineb (95% CI)	95 –1.1 –2.6 (-3.2, –2.0) c	92 1.6 or

a Intent to treat population – last observation carried forward

b Adjusted mean

c P<0.05 for treatment difference

xAJS

In patients who were treated for at least 104 weeks, the adjusted mean change in baseline in HbA1c was –0.97% for Eperzan (N = 182) and –1.04% for insulin glargine (N = 102). The adjusted mean change in body weight from baseline at 104 weeks was –2.6 kg for Eperzan (N = 184) and +1.4 kg for insulin glargine (N = 104). These data exclude the use of antidiabetic therapies permitted after the efficacy assessment if glycaemic thresholds were exceeded.

Active-controlled study versus liraglutide in combination with metformin, thiazolidinedione, or sulphonylurea (as monotherapy or dual therapy)

The efficacy of Eperzan was evaluated in a 32-week, randomised, open-label, liraglutide-controlled noninferiority study (N = 805). Eperzan 30 mg SC weekly (with uptitration to 50 mg weekly at Week 6) was compared to liraglutide 1.8 mg daily (titrated up from 0.6 mg at Week 1 and 1.2 mg at Week 1 to Week 2) in patients inadequately controlled on monotherapy or combination oral antidiabetic therapy (metformin, thiazolidinedione, or sulphonylureas). The primary endpoint was change in HbA1c from baseline at 32 weeks.

Treatment with Eperzan did not meet the pre-specified noninferiority margin (0.3%) against liraglutide for HbA1c (see Table 8).

Table 8. Results of an active-controlled trial of Eperzan 30 mg SC weekly (with uptitration to 50 mg weekly) versus liraglutide 1.8 mg daily at 32 weeksa

	Eperzan 30 mg/50 mg Weekly	Liraglutide 1.8 mg Daily
Intent to Treat Population (N)	402	403
HbA1c (%)
Baseline (mean) Change at Week 32b Difference from liraglutideb (95% CI) P value (noninferiority)	8.2 –0.8 0.2 (0.1, 0.3) p = 0.0846	8.2 –1.0
Proportion Achieving HbA1c <7%	42%	52%
Body Weight (kg)
Baseline (mean) Change at Week 32b Difference from liraglutideb (95% CI)	92 –0.6 1.55 (1.05, 2.06) c	93 –2.2

a Intent to treat population – last observation carried forward b Adjusted mean

c P<0.05 for treatment difference

Active-controlled study versus sitagliptin in  patients with type 2 diabetes and different degrees of renal impairment

The efficacy of Eperzan was evaluated in a randomised, double-blind, active-controlled 52-week study in 486 patients with mild, moderate, and severe renal impairment inadequately controlled on a current regimen of diet and exercise or other antidiabetic therapy. Eperzan 30 mg SC weekly (with uptitration to 50 mg weekly if needed) was compared to sitagliptin. Sitagliptin was dosed according to creatinine clearance estimated by Cockcroft-Gault formula (100 mg daily in mild, 50 mg daily in moderate, and 25 mg daily in severe renal impairment) The primary endpoint was change in HbAic from baseline at 26 weeks.

Treatment with Eperzan resulted in statistically significant reductions in HbAic from baseline at Week 26 compared to sitagliptin. The model-adjusted mean decrease in HbAic from baseline with Eperzan was –0.80 (n = 125), –0.83 (n = 98), and –1.08 (n = 19) ii patients with mild (eGFR 60 to 89 ml/min/1.73m2), moderate (eGFR 30 to 59 ml/min/1.73m2), and severe (eGFR <30 ml/min/1.73m2) renal impairment, respectively (see Table 9).

Table 9. Results at 26 weeks in a study of Eperzan 30 mg SC weekly (with uptitration to 50 mg weekly if needed) versus sitagliptin (dosed according to renal function) in patients with different degrees of renal impairment

	Eperzan 30 mg/50 mg Weekly	Sitagliptin
Intent to Treat Population (N)	246 (125 mild, 98 moderate, 19 severe)a	240 (122 mild, 99 moderate, 15 severe)a
HbA1c (%)
Baseline (mean) Change at Week 26b Difference from sitagliptinb (95% CI)	8.1 –0.8 –0.3 (-0.5, –0.2)c	8.2 –0.5
Proportion Achieving HbA1c <7%	43%	31%
Body Weight (kg)
Baseline (mean) Change at Week 26b Difference from sitagliptinb (95% CI)	84 –0.8 –0.6 (-1.1, –0.1)c	83 –0.19

a Intent to treat population – Last Observation Carried Forward (ITT-LOCF) b Adjusted mean

c P<0.05 for treatment difference

Durability of glycaemic control

The durability of glycaemic control for Eperzan over time relative to other classes of type 2 antidiabetic agents and placebo is shown in Figure 1 as add-on to metformin.

Figure 1: Kaplan-Meier curve showing durability of glycaemic control (measured by time to rescue) for Eperzan, relative to two active controls (sitagliptin and glimepiride) and placebo

x axis; Weeks (Rescue free), y axis; Probability of event

Fasting plasma glucose

Treatment with Eperzan alone or in combination with one or two oral antidiabetic medicinal products resulted in a reduction in fasting plasma glucose from baseline as compared to placebo of 1.3 to 2.4 mmol/l. Most of this reduction was observed within the first two weeks of treatment.

Cardiovascular Evaluation:

A meta-analysis of 9 clinical studies (8 major effectiveness studies and 1 phase II dose finding study) of up to 3 years duration was conducted to assess the cardiovascular safety of Eperzan (N=2,524) compared to all comparators (N=2,583) within these trials. An endpoint called MACE+ (major adverse cardiac events plus) included hospitalisation for unstable angina in addition to the MACE endpoints (acute myocardial infarction, stroke, and CV death). The hazard ratio for Eperzan versus comparators for MACE+ was 1.0 (95% CI 0.68, 1.49). The incidence rates observed for first MACE+ were 1.2 and 1.1 events per 100 person-years for Eperzan versus all comparators, respectively.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of studies with Eperzan in one or more subsets of the paediatric population in the treatment of type 2 diabetes mellitus (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Following SC administration of a single 30 mg dose to subjects with type 2 diabetes, maximum concentrations were reached 3 to 5 days post dose with mean peak albiglutide concentration (Cmax) of 1.74 mcg/ml and mean area under the time-concentration curve (AUC) of 465 mcg.h/ml. The average weekly steady state concentrations following SC administration of 30 mg or 50 mg albiglutide estimated in the population PK analyses from phase III patient studies were approximately 2.6 mcg/ml and 4.4 mcg/ml, respectively. Steady-state exposures are achieved following 3–5 weeks of once-weekly administration.

Exposures at the 30 mg and 50 mg dose levels were consistent with a dose-proportional increase. However, in healthy volunteers following 50 mg the steady state concentration was 7.39 ^g/ml at day 36, thus higher than population PK analyses from phase III patient studies predicted. Similar exposure is achieved with SC administration of albiglutide in the abdomen, thigh, or upper arm.

Distribution

The mean estimate of apparent volume of distribution of albiglutide following SC administration is 11 litres. As albiglutide is an albumin fusion molecule, plasma protein binding has not been assessed.

Biotransformation

Albiglutide is a protein for which the expected metabolic pathway is degradation to small peptides and individual amino acids by ubiquitous proteolytic enzymes.

Elimination

The mean apparent clearance of albiglutide is 67 ml/h with an elimination half-life of approximately 5 days based on estimations from the population PK analyses from phase III patient studies and measured values.

Special populations

Patients with renal impairment

In a population pharmacokinetic analysis including a phase III trial in patients with mild, moderate and severe renal impairment, exposures were increased by approximately 30 to 40% in severe renal impairment compared to those observed in type 2 diabetic patients with normal renal function. In addition, a clinical pharmacology study showed a similar increased exposure for patients with moderate or severe renal impairment or those on haemodialysis relative to patients without renal impairment. These differences were not considered clinically relevant (see section 4.2).

Patients with hepatic insufficiency

No clinical studies were conducted to examine the effects of hepatic impairment on the pharmacokinetics of Eperzan. Therapeutic proteins such as albiglutide are catabolised by widely distributed proteolytic enzymes, which are not restricted to hepatic tissue; therefore, changes in hepatic function are unlikely to have any effect on the elimination of Eperzan (see section 4.2).

Gender

Based on the results of population pharmacokinetic analyses, there is no clinically relevant effect of gender on clearance.

Race and ethnicity

Based on the results of population pharmacokinetic analyses that included Caucasian, African American/African, Asian and Hispanic/Non-Hispanic patients, race and ethnicity had no clinically meaningful effect on the pharmacokinetics of Eperzan clearance.

Japanese patients showed approximately 30 to 40% higher exposures than Caucasians, likely attributable to lower body weight. This effect was not considered clinically relevant.

Elderly patients (>65 years)

Age had no clinically relevant effect on the pharmacokinetics of albiglutide based on a population pharmacokinetic analysis of subjects aged 24–83 years (see section 4.2).

Body weight

Body weight has no clinically relevant effect on albiglutide AUC over the range 44 to 158 kg. A 20% increase in body weight resulted in an approximate 18.5% increase in clearance.

Paediatric population:

No pharmacokinetic data are available in paediatric patients.

5.3 Preclinical safety data

Non-clinical data reveal no special hazards for humans based on studies of safety pharmacology or repeatdose toxicity. As albiglutide is a recombinant protein, no genotoxicity studies have been conducted.

In a 52-week monkey study, there was a small increase in pancreas tissue weight at 50 mg/kg/week (75 times clinical exposure based on AUC) associated with acinar cell hypertrophy. A small increase in islet cell number was also observed. The pancreas changes were not associated with histomorphologic abnormalities or evidence of increased proliferation.

No carcinogenicity studies have been performed with albiglutide due to immunogenicity in rodents. Thyroid C-cell tumours were observed in 2 year rodent carcinogenicity studi es with other GLP-1 receptor agonists. Increased serum calcitonin levels have been associated with the thyroid C-cell hyperplasia and tumours observed in rodent studies with these other agents. Albiglutid e also produced dose-dependent increases in serum calcitonin levels in a 21-day study in mice, suggesting that thyroid tumours in rodents are a theoretical possibility for albiglutide as well. There were no albiglutide related findings in thyroids of monkeys given up to 50 mg/kg/week for up to 52 weeks (75 times clinicj exposure based on AUC). The clinical relevance of the observed thyroid C-cell tumours in rodents is unknown.

In reproductive toxicology studies with albiglutide in mice, there were no effects on mating or fertility at doses up to 50 mg/kg/day (at low multip’e of clinical exposure). Reductions in oestrous cycles were observed at 50 mg/kg/day, a dose associated with maternal toxicity (body weight loss and reduced food consumption). Effects on embryo-foetal development (embryo-foetal lethality and skeletal variations) were observed at 50 mg/kg/day (at low multiple of clinical exposure). Offspring of mice dosed with 50 mg/kg/day during organogenesis had reduced weight during the pre-weaning period (which recovered after weaning), dehydration and coldness, and a delay in balanopreputial separation. No effects were seen at 5 mg/kg/day (at exposures similar to clinical exposure).

In pre- and postnatal development studies in mice administered albiglutide during pregnancy or while nursing, reduced pre-weaning body weight of F1 offspring was observed at >1 mg/kg/day (at exposures below clinical exposure). Reduced F1 body weight reversed post-weaning with the exception of F1 females from dams treated perinatally (end of gestation to 10 days postpartum) at >5 mg/kg/day with no other effects on development. Trace levels of albiglutide were detected in plasma of offspring. It is unknown whether the reduced offspring body weight was caused by a direct albiglutide effect on the offspring or secondary to effects on the dam.

Increased mortality and morbidity were seen at all doses (>1 mg/kg/day) in lactating females in mouse pre-and postnatal development studies. Mortalities have not been observed in previous toxicology studies in nonlactating or non-pregnant mice, nor in pregnant mice. These findings are consistent with lactational ileus syndrome which has been previously reported in mice. Since the relative stress of lactation energy demands is much lower in humans than mice and humans have large energy reserves, the mortalities observed in lactating mice are considered not relevant to humans.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Powder for solution for injection:

Sodium dihydrogen phosphate monohydrate

Disodium phosphate, anhydrous

Trehalose dihydrate

Mannitol (E421)

Polysorbate 80

Solvent:

Water for injections

6.2 Incompatibilities

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

6.3 Shelf life

3 years.

After reconstitution, the pen should be used within 8 hours. Use the pen immediately after the needle is attached otherwise the solution can dry inside the needle and block it.

6.4 Special precautions for storage

Store refrigerated at 2°C to 8°C. Do not freeze.

Patients may store the pens at room temperature, not exceeding 30°C, for no more than a total of 4 weeks prior to use. At the end of this period the pen should be used or discarded.

For shelf life of the reconstituted product, see section 6.3.

6.5 Nature and contents of container

Dual Chamber Cartridge (DCC) composed of a Type 1 glass barrel sealed with bromobutyl rubber stoppers and a bromobutyl rubber closure disc encased in a polypropylene snap on cap. Each cartridge is assembled into a disposable single use plastic pen injector (pen).

Each pen delivers a single 30 mg or 50 mg dose of Eperzan in a volume of 0.5 ml.

Pack sizes:

Carton of 4 single-dose pens and 4 pen needles.

Multipack containing 12 single-dose pens and 12 pen needles (3 packs of 4 pens and 4 needles).

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Instructions for use

Eperzan that has been frozen must not be used.

Inspect the pen to ensure that the number ‘1’ is visible in the number window. Do not use the pen if the number ‘1’ is not showing.

Reconstitution and administration by the patient

Full instructions for reconstitution and administration to be used by the patient are provided in the Instructions for Use section of the Package Leaflet.

Instruct the patient to read the full Instructions for Use (IFU) including the Questions and Answers before starting the therapy and refer back to the IFU each time before injecting the dose.

Alternate method of reconstitution (healthcare professional use only)’^

The Instructions for Use included in the Package Leaflet provide directions for the patient to wait 15 minutes for the 30 mg pen and 30 minutes for the 50 mg pen after the lyophilised powder and diluent are mixed to ensure reconstitution. Healthcare professionals may utilise the following alternate method of reconstitution that allows for more rapid dissolution. Because this method relies on appropriate swirling and visual inspection of the solution, it is intended only for healthcare professionals.

Inspect the pen for ‘1’ in the number window and expiration date. Follow instructions to twist the cartridge until ‘2’ appears in the number window and a “c’ick” is heard. This mixes the diluent in the rear chamber of the cartridge with the lyophilised powder in the front chamber. With the clear cartridge pointing up, gently swirl the pen for one minute. Avoid shaking as this can result in foaming. Inspect, and continue to swirl the pen until all the powder is dissolved. Complete dissolution for the 30 mg pen usually occurs within 2 minutes but may take up to 5 minutes, as confirmed by visual inspection for a clear solution free of particles. Complete dissolution for the 50 mg pen usually occurs within 7 minutes but may take up to 10 minutes. A small amount of foam on top of the solution at the end of the reconstitution is normal. After reconstitution, continue to follow the steps in th instructions for use to attach the needle, prime the pen injector and administer the injection.

Use Eperzan only if it is a clear yellow solution and contains no particles.

7. MARKETING AUTHORISATION HOLDER

GlaxoSmithKline Trading Services Limited,

Currabinny,

Carrigaline,

County Cork,

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/13/908/001

EU/1/13/908/002

EU/1/13/908/003

EU/1/13/908/004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 March 2014