This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each dose (0.2 ml) contains 10 micrograms (mcg) of lixisenatide (50 mcg per ml). Excipient(s) with known effects: Each dose contains 54 micrograms of metacresol. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

CLINICAL PARTICULARS

Posology and method of administration

Starting dose: dosing is initiated at 10 mcg Lyxumia once daily for 14 days. Maintenance dose: a fixed maintenance dose of 20 mcg Lyxumia once daily is started on Day 15. Lyxumia 20 micrograms solution for injection is available for the maintenance dose. Lyxumia is administered once daily, within the hour prior to the first meal of the day or the evening meal. If a dose of Lyxumia is missed, it should be injected within the hour prior to the next meal. When Lyxumia is added to existing metformin therapy, the current metformin dose can be continued unchanged. When Lyxumia is added to existing therapy of a sulphonylurea or a basal insulin, a reduction in the dose of the sulphonylurea or the basal insulin may be considered to reduce the risk of hypoglycaemia. Lyxumia should not be given in combination with basal insulin and a sulphonylurea due to increased risk of hypoglycaemia (see section 4.4). The use of Lyxumia does not require specific blood glucose monitoring. However, when used in combination with a sulphonylurea or a basal insulin, blood glucose monitoring or blood glucose self-monitoring may become necessary to adjust the doses of the sulphonylurea or the basal insulin.

No dose adjustment is required based on age. The clinical experience in patients >=75 years is limited (see sections 5.1 and 5.2).

No dose adjustment is required for patients with mild renal impairment (creatinine clearance : 50-80 ml/min). There is limited therapeutic experience in patients with moderate renal impairment (creatinine clearance: 30-50 ml/min) and Lyxumia should be used with caution in this population. There is no therapeutic experience in patients with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease and therefore, it is not recommended to use Lyxumia in these populations (see section 5.2).

No dose adjustment is needed in patients with hepatic impairment (see section 5.2)

The safety and efficacy of lixisenatide in children and adolescents less than 18 years of age have not yet been established. No data are available.

Lyxumia is to be injected subcutaneously in the thigh, abdomen or upper arm. Lyxumia should not be administered intravenously or intramuscularly.

Contraindications

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

Special warnings and precautions for use

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

Use of glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with a risk of developing acute pancreatitis. Patients should be informed of the characteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis is suspected, lixisenatide should be discontinued ; if acute pancreatitis is confirmed, lixisenatide should not be restarted. Caution should be exercised in patients with a history of pancreatitis.

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

There is limited therapeutic experience in patients with moderate renal impairment (creatinine clearance: 30-50 ml/min) and no therapeutic experience in patients with severe renal impairment (creatinine clearance less than 30 ml/min) or end-stage renal disease. Lyxumia should be used with caution in patients with moderate renal impairment. Use is not recommended in patients with severe renal impairment or end-stage renal disease (see sections 4.2 and 5.2).

Patients receiving Lyxumia with a sulphonylurea or with a basal insulin may have an increased risk of hypoglycaemia. Reduction of the dose of the sulphonylurea or the basal insulin may be considered to reduce the risk of hypoglycaemia (see section 4.2). Lyxumia should not be given in combination with basal insulin and a sulphonylurea due to increased risk of hypoglycaemia.

The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally administered medicinal products. Lyxumia should be used with caution in patients receiving oral medicinal products that require rapid gastrointestinal absorption, require careful clinical monitoring or have a narrow therapeutic ratio. Specific recommendations regarding intake of such medicinal products are given in section 4.5.

Lixisenatide has not been studied in combination with dipeptidyl peptidase 4 (DPP-4) inhibitors. There is limited experience in patients with congestive heart failure.

Patients treated with Lyxumia should be advised of the potential risk of dehydration in relation to gastrointestinal adverse reactions and take precautions to avoid fluid depletion.

Interaction with other medicinal products and other forms of interaction

Lixisenatide is a peptide and is not metabolised by cytochrome P450. In in vitro studies, lixisenatide did not affect the activity of cytochrome P450 isozymes or human transporters tested. The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally administered medicinal products. Patients receiving medicinal products of either a narrow therapeutic ratio or medicinal products that require careful clinical monitoring should be followed closely, especially at the time of initiation of lixisenatide treatment. These medicinal products should be taken in a standardised way in relation to lixisenatide. If such medicinal products are to be administered with food, patients should be advised to, if possible, take them with a meal when lixisenatide is not administered. For oral medicinal products that are particularly dependent on threshold concentrations for efficacy, such as antibiotics, patients should be advised to take those medicinal products at least 1 hour before or 4 hours after lixisenatide injection. Gastro-resistant formulations containing substances sensitive to stomach degradation, should be administered 1 hour before or 4 hours after lixisenatide injection.

Paracetamol was used as a model medicinal product to evaluate the effect of lixisenatide on gastric emptying. Following administration of a single dose of paracetamol 1000 mg, paracetamol AUC and t1/2 were unchanged whatever the timing of its administration (before or after the lixisenatide injection). When administered 1 or 4 hours after 10 mcg lixisenatide, Cmax of paracetamol was decreased by 29% and 31% respectively and median tmax was delayed by 2.0 and 1.75 hours respectively. A further delay in tmax and a reduced Cmax of paracetamol have been predicted with the 20 mcg maintenance dose. No effects on paracetamol Cmax and tmax were observed when paracetamol was administered 1 hour before lixisenatide. Based on these results, no dose adjustment for paracetamol is required but the delayed tmax observed when paracetamol is administered 1-4 hours after lixisenatide should be taken into account when a rapid onset of action is required for efficacy.

Following administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol 0.03 mg/levonorgestrel 0.15 mg) 1 hour before or 11 hours after 10 mcg lixisenatide, the Cmax, AUC, t1/2 and tmax of ethinylestradiol and levonorgestrel were unchanged. Administration of the oral contraceptive 1 hour or 4 hours after lixisenatide did not affect AUC and t1/2 of ethinylestradiol and levonorgestrel, whereas Cmax of ethinylestradiol was decreased by 52% and 39% respectively and Cmax of levonorgestrel was decreased by 46% and 20%, respectively and median tmax was delayed by 1 to 3 hours. The reduction in Cmax is of limited clinical relevance and no dose adjustment for oral contraceptives is required.

When lixisenatide 20 mcg and atorvastatin 40 mg were co-administered in the morning for 6 days, the exposure to atorvastatin was not affected, while Cmax was decreased by 31% and tmax was delayed by 3.25 hours. No such increase for tmax was observed when atorvastatin was administered in the evening and lixisenatide in the morning but the AUC and Cmax of atorvastatin were increased by 27% and 66% respectively. These changes are not clinically relevant and therefore, no dose adjustment for atorvastatin is required when co-administered with lixisenatide.

After concomitant administration of warfarin 25 mg with repeated dosing of lixisenatide 20 mcg, there were no effects on AUC or INR (International Normalised Ratio) while Cmax was reduced by 19% and tmax was delayed by 7 hours. Based on these results, no dose adjustment for warfarin is required when co-administered with lixisenatide; however, frequent monitoring of INR in patients on warfarin and/or coumarin derivatives is recommended at the time of initiation or ending of lixisenatide treatment.

After concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg at steady state, the AUC of digoxin was not affected. The tmax of digoxin was delayed by 1.5 hour and the Cmax was reduced by 26%. Based on these results, no dose adjustment for digoxin is required when co-administered with lixisenatide.

After concomitant administration of lixisenatide 20 mcg and ramipril 5 mg during 6 days, the AUC of ramipril was increased by 21% while the Cmax was decreased by 63%. The AUC and Cmax of the active metabolite (ramiprilat) were not affected. The tmax of ramipril and ramiprilat were delayed by approximately 2.5 hours. Based on these results, no dose adjustment for ramipril is required when co-administered with lixisenatide.

Fertility, pregnancy and lactation

Lyxumia is not recommended in women of childbearing potential not using contraception.

There are no adequate data from the use of Lyxumia in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Lyxumia should not be used during pregnancy. The use of insulin is recommended instead. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Lyxumia should be discontinued.

It is unknown if Lyxumia is excreted in human milk. Lyxumia should not be used during breast-feeding.

Animal studies do not indicate direct harmful effects with respect to fertility.

Effects on ability to drive and use machines

Lyxumia has no or negligible influence on the ability to drive or use machines. When used in combination with a sulphonylurea or a basal insulin, patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines.

Undesirable effects

Summary of the safety profile

Over 2,600 patients have received Lyxumia either alone or in combination with metformin, a sulphonylurea (with or without metformin) or a basal insulin (with or without metformin, or with or without a sulphonylurea) in 8 large placebo- or active-controlled phase III studies. The most frequently reported adverse reactions during clinical studies were nausea, vomiting and diarrhoea. These reactions were mostly mild and transient. In addition, hypoglycaemia (when Lyxumia was used in combination with a sulphonylurea and/or a basal insulin) and headache occurred. Allergic reactions have been reported in 0.4% of Lyxumia patients.

Tabulated list of adverse reactions

Adverse reactions reported from placebo- and active-controlled phase III studies over the entire treatment period are presented in Table 1. The table presents adverse reactions that occurred with an incidence >5% if the frequency was higher among Lyxumia treated patients than patients treated with all comparators. The table also includes adverse reactions with a frequency >=1% in the Lyxumia group if the frequency was greater than 2 times the frequency for all comparators group. Frequencies of adverse reactions 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). Within each system organ class, adverse reactions are presented in order of decreasing frequency. Table 1: Adverse reactions reported in placebo- and active-controlled phase III studies during the entire treatment period (including the period beyond the main 24-week treatment period in studies with >=76 weeks of total treatment).

System Organ Class	Frequency of occurrence
	Very common	Common	Uncommon
Infections and infestations		Influenza Upper respiratory tract infection Cystitis Viral infection
Immune system disorders			Anaphylactic reaction
Metabolism and nutrition disorders	Hypoglycaemia (in combination with a sulphonylurea and / or a basal insulin)	Hypoglycaemia (in combination with metformin alone)
Nervous system disorders	Headache	Dizziness Somnolence
Gastrointestinal disorders	Nausea Vomiting Diarrhoea	Dyspepsia
Skin and subcutaneous tissue disorders			Urticaria
Musculoskeletal and connective tissue disorders		Back pain
General disorders and administration site conditions		Injection site pruritus

Description of selected adverse reactions

Hypoglycaemia

In patients taking Lyxumia in monotherapy, symptomatic hypoglycaemia occurred in 1.7% of lixisenatide treated patients and in 1.6% of placebo treated patients. When Lyxumia is used in combination with metformin alone, symptomatic hypoglycaemia occurred in 7.0% of lixisenatide patients and in 4.8% of placebo patients during the entire treatment period. In patients taking Lyxumia in combination with a sulphonylurea and metformin, symptomatic hypoglycaemia occurred in 22.0% of lixisenatide treated patients and in 18.4% of placebo treated patients during the entire treatment period (3.6% absolute difference). When Lyxumia is used in combination with a basal insulin with or without metformin, symptomatic hypoglycaemia occurred in 42.1% of lixisenatide patients and in 38.9% of placebo patients during the entire treatment period (3.2% absolute difference). During the entire treatment period, when Lyxumia was given with a sulphonylurea alone, symptomatic hypoglycaemia occurred in 22.7% of lixisenatide treated patients versus 15.2% with placebo (7.5% absolute difference). When Lyxumia was given with a sulphonylurea and a basal insulin, symptomatic hypoglycaemia occurred in 47.2% of lixisenatide treated patients compared to 21.6% with placebo (25.6% absolute difference). Overall, the incidence of severe symptomatic hypoglycaemia was uncommon (0.4% in lixisenatide patients and 0.2% in placebo patients) during the entire treatment period of the Phase III placebo-controlled studies.

Gastrointestinal disorders

Nausea and vomiting were the most frequently reported adverse reactions during the main 24-week treatment period. The incidence of nausea was higher in the lixisenatide group (26.1%) compared to the placebo group (6.2%) and the incidence of vomiting was higher in the lixisenatide group (10.5%) than in the placebo group (1.8%). They were mostly mild and transient and occured during the first 3 weeks after starting treatment. Thereafter, they progressively decreased during the following weeks.

Injection site reactions

Injections site reactions were reported in 3.9% of the patients receiving Lyxumia while they were reported in 1.4% of patients receiving placebo during the main 24-week treatment period. The majority of reactions were mild in intensity and usually did not result in discontinuation of the treatment.

Immunogenicity

Consistent with the potentially immunogenic properties of medicinal products containing proteins or peptides, patients may develop anti-lixisenatide antibodies following treatment with Lyxumia and, at the end of the main 24-week treatment period in placebo-controlled studies, 69.8% of lixisenatide patients had a positive antibody status. The percentage of patients who were antibody positive was similar at the end of the entire 76-week treatment period. At the end of the main 24-week treatment period, 32.2% of the patients having a positive antibody status had an antibody concentration above the lower limit of quantification, and at the end of the entire 76-week treatment period, 44.7% of the patients had an antibody concentration above the lower limit of quantification. After stopping the treatment, few antibody positive patients were followed-up for antibody status; the percentage decreased to approximately 90% within 3 months and 30% at 6 months or beyond. The change in HbA1c from baseline was similar regardless of the antibody status (positive or negative). Of lixisenatide-treated patients with HbA1c measurement, 79.3% had either a negative antibody status or an antibody concentration below the lower limit of quantification and the other 20.7% of patients had a quantified antibody concentration. In the subset of patients (5.2%) with the highest antibody concentrations, the mean improvement in HbA1c at Week 24 and at Week 76 was in a clinically relevant range; however there was variability in the glycaemic response and 1.9% had no decrease in HbA1c. The antibody status (positive or negative) is not predictive of the reduction of HbA1c for an individual patient. There was no difference in the overall safety profile in patients regardless of the antibody status with the exception of an increase of the incidence of injection site reactions (4.7% in antibody positive patients compared to 2.5% in antibody-negative patients during the entire treatment period). The majority of injection site reactions were mild, regardless of antibody status. There was no cross-reactivity versus either native glucagon or endogenous GLP-1.

Allergic reactions

Allergic reactions possibly associated with lixisenatide (such as anaphylactic reaction, angioedema and urticaria) have been reported in 0.4% of lixisenatide patients while possibly associated allergic reactions occurred in less than 0.1% of placebo patients during the main 24-week treatment period. Anaphylactic reactions were reported in 0.2% of the lixisenatide treated patients vs. none in the placebo group. Most of these reported allergic reactions were mild in severity. One case of anaphylactoid reaction was reported during clinical trials with lixisenatide.

Heart rate

In a study in healthy volunteers, a transient rise in heart rate has been observed after administration of lixisenatide 20 mcg. Cardiac arrhythmias particularly tachycardia (0.8% vs <0.1%) and palpitations (1.5% vs 0.8%) have been reported in lixisenatide patients compared to placebo treated patients.

Withdrawal

The incidence of treatment discontinuation due to adverse events was 7.4% for Lyxumia compared to 3.2% in the placebo group during the main 24-week treatment period. The most common adverse reactions which led to treatment discontinuation in the lixisenatide group were nausea (3.1%) and vomiting (1.2%).

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.

Overdose

During clinical studies, doses up to 30 mcg of lixisenatide twice a day were administered to type 2 diabetic patients in a 13-week study. An increased incidence of gastrointestinal disorders was observed. In case of overdose, appropriate supportive treatment should be initiated according to the patient's clinical signs and symptoms and the lixisenatide dose should be reduced to the prescribed dose.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

Pharmacotherapeutic group: Other blood glucose lowering drugs, excl. insulins, ATC code: A10BX10.

Lixisenatide is a selective GLP-1 receptor agonist. The GLP-1 receptor is the target for native GLP-1, an endogenous incretin hormone that potentiates glucose-dependent insulin secretion from the pancreatic beta cells. Lixisenatide action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in intracellular cyclic adenosine monophosphate (cAMP). Lixisenatide stimulates insulin secretion when blood glucose is increased but not at normoglycaemia, which limits the risk of hypoglycaemia. In parallel, glucagon secretion is suppressed. In case of hypoglycaemia, the rescue mechanism of glucagon secretion is preserved. Lixisenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appears in the circulation.

When administered once daily, lixisenatide improves glycaemic control through the immediate and sustained effects of lowering both post-prandial and fasting glucose concentrations in patients with type 2 diabetes. This effect on post-prandial glucose was confirmed in a 4-week study versus liraglutide 1.8 mg once a day. Reduction from baseline in the AUC 0:30-4:30h of plasma glucose after a test-meal was: -227.25 h *mg/dL (-12,61 h *mmol/L) in the lixisenatide group and -72.83 h *mg/dL (- 4.04 h *mmol/L) in the liraglutide group.

The effects of Lyxumia on glycaemic control were evaluated in six randomised double-blind, placebo-controlled clinical studies and one randomised, open-label, active-controlled study versus exenatide. These studies included 3,825 patients with type 2 diabetes (2,445 patients randomised to lixisenatide), 48.2% men and 51.8% women. 768 subjects (447 randomised to lixisenatide) were >=65 years of age and 103 subjects (57 randomised to lixisenatide) were >=75 years of age. In the completed Phase III studies, it was observed that more than 90% of the patient population was able to remain on the once daily maintenance dose of 20 mcg Lyxumia at the end of the main 24-week treatment period.

Lyxumia in combination with metformin, a sulphonylurea, pioglitazone or a combination of these agents showed statistically significant reductions in HbA1c, in fasting plasma glucose and in 2-hour post-prandial glucose after a test-meal compared to placebo at the end of the main 24-week treatment period (tables 2 and 3). The HbA1c reduction was significant with once-daily administration, whether administered morning or evening. This effect on HbA1c was sustained in long term studies for up to 76 weeks.

Table 2: Placebo-controlled studies in combination with metformin (24-week results). Metformin as background therapy

In an active-controlled study, Lyxumia once daily showed an HbA1c reduction of -0.79% compared to -0.96% with exenatide twice daily at the end of the main 24-week treatment period with a mean treatment difference of 0.17% (95% CI: 0.033, 0.297) and a similar percentage of patients achieved an HbA1c less than 7% in the lixisenatide group (48.5%) and in the exenatide group (49.8%). The incidence of nausea was 24.5% in the lixisenatide group compared to35.1% in the exenatide twice daily group and the incidence of symptomatic hypoglycaemia with lixisenatide was 2.5% during the 24-week main treatment period compared to 7.9% in the exenatide group.

Table 3: Placebo-controlled study in combination with a sulphonylurea (24-week results) Sulphonylurea as background therapy with or without metformin

Mean HbA1c (%)

Patients (%) achieving

HbA1c <7.0%

Mean body weight (kg)

In a clinical study, the addition of lixisenatide to pioglitazone with or without metformin, in patients not adequately controlled with pioglitazone, resulted in an HbA1c decrease from baseline of 0.90%, compared to a decrease from baseline of 0.34% in the placebo group at the end of the 24-week main treatment period. At the end of the 24-week main treatment period, 52.3% of the lixisenatide patients achieved an HbA1c less than 7 % compared to 26.4% in the placebo group. During the 24-week main treatment period, nausea was reported in 23.5% in the lixisenatide group compared to 10.6% in the placebo group and symptomatic hypoglycaemia was reported in 3.4% of the lixisenatide patients compared to 1.2% in the placebo group.

Lyxumia given with a basal insulin alone, or with a combination of a basal insulin and metformin, or a combination of a basal insulin and a sulphonylurea resulted in statistically significant reductions in HbA1c and in 2-hour post-prandial glucose after a test-meal compared to placebo. Table 4: Placebo-controlled studies in combination with a basal insulin (24-week results) Basal insulin as background therapy Alone or in combination with metformin Basal insulin as background therapy Alone or in combination with a sulphonylurea *

Lixisenatide 20 mcg (N= 160)		Placebo (N= 159)	Lixisenatide 20 mcg Morning Evening (N= 255) (N= 255)		Placebo (N= 170)
Mean HbA 1c (%)			8.07	8.07	8.02
Baseline	7.99	8.03	8.07	8.07	8.02
LS mean change from baseline	-0.92	-0.42	-0.87	-0.75	-0.38
Patients (%) achieving HbA 1c
<7.0%	47.4	24.1	43.0	40.6	22.0
Mean body weight (kg)
Baseline	90.30	87.86	90.14	89.01	90.40
LS mean change from baseline	-2.63	-1.63	-2.01	-2.02	-1.64

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS