LYXUMIA 20mcg 100mcg / ml injectible solution medication leaflet

Lyxumia 10 micrograms solution for injection

Lyxumia 20 micrograms solution for injection

Lyxumia 10 micrograms solution for injection

Each dose (0.2 ml) contains 10 micrograms (mcg) of lixisenatide (50 mcg per ml).

Lyxumia 20 micrograms solution for injection

Each dose (0.2 ml) contains 20 micrograms (mcg) of lixisenatide (100 mcg per ml).

Excipient(s) with known effects

Each dose contains 540 micrograms of metacresol.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Clear, colourless solution.

Lyxumia is indicated for the treatment of adults with type 2 diabetes mellitus to achieve glycaemiccontrol in combination with oral glucose-lowering medicinal products and/or basal insulin when these,together, with diet and exercise, do not provide adequate glycaemic control (see sections 4.4 and 5.1for available data on the different combinations).

Starting dose: dosing is initiated at 10 mcg lixisenatide once daily for 14 days.

Maintenance dose: a fixed maintenance dose of 20 mcg lixisenatide once daily is started on Day 15.

For the starting dose Lyxumia 10 micrograms solution for injection is available.

For the maintenance dose Lyxumia 20 micrograms solution for injection is available.

When Lyxumia is added to existing metformin therapy, the current metformin dose can be continuedunchanged.

When Lyxumia is added to existing therapy of a sulphonylurea or a basal insulin, a reduction in thedose 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 increasedrisk of hypoglycaemia (see section 4.4).

The use of Lyxumia does not require specific blood glucose monitoring. However, when used incombination with a sulphonylurea or a basal insulin, blood glucose monitoring or blood glucoseself-monitoring may become necessary to adjust the doses of the sulphonylurea or the basal insulin.

No dose adjustment is required based on age.

No dose adjustment is required for patients with mild or moderate renal impairment.

There is no therapeutic experience in patients with severe renal impairment (creatinine clearance lessthan 30 ml/min) or end-stage renal disease and therefore, it is not recommended to use lixisenatide inthese 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 notbeen established (see section 5.1). No data are available.

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

The injection is administered once daily, within the hour prior to any meal of the day. It is preferablethat the prandial injection of Lyxumia is performed before the same meal every day, when the mostconvenient meal has been chosen. If a dose is missed, it should be injected within the hour prior to thenext meal.

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

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

Use of glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with a risk ofdeveloping acute pancreatitis. There have been few reported events of acute pancreatitis withlixisenatide although a causal relationship has not been established. Patients should be informed of thecharacteristic symptoms of acute pancreatitis: persistent, severe abdominal pain. If pancreatitis issuspected, lixisenatide should be discontinued; if acute pancreatitis is confirmed, lixisenatide shouldnot be restarted. Caution should be exercised in patients with a history of pancreatitis.

Severe gastrointestinal disease

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

There is no therapeutic experience in patients with severe renal impairment (creatinine clearance lessthan 30 ml/min) or end-stage renal disease. Use is not recommended in patients with severe renalimpairment 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 ofhypoglycaemia. Reduction of the dose of the sulphonylurea or the basal insulin may be considered toreduce the risk of hypoglycaemia (see section 4.2). Lixisenatide should not be given in combinationwith 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 orallyadministered medicinal products. Lixisenatide should be used with caution in patients receiving oralmedicinal products that require rapid gastrointestinal absorption, require careful clinical monitoring orhave a narrow therapeutic ratio. Specific recommendations regarding intake of such medicinalproducts are given in section 4.5.

Lixisenatide has not been studied in combination with dipeptidyl peptidase 4 (DPP-4) inhibitors.

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

This medicinal product contains metacresol, which may cause allergic reactions.

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

Lixisenatide is a peptide and is not metabolised by cytochrome P450. In in vitro studies, lixisenatidedid 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 orallyadministered medicinal products. Patients receiving medicinal products of either a narrow therapeuticratio 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 takenin a standardised way in relation to lixisenatide. If such medicinal products are to be administered withfood, patients should be advised to, if possible, take them with a meal when lixisenatide is notadministered.

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 beforeor 4 hours after lixisenatide injection.

Gastro-resistant formulations containing substances sensitive to stomach degradation, should beadministered 1 hour before or 4 hours after lixisenatide injection.

Paracetamol was used as a model medicinal product to evaluate the effect of lixisenatide on gastricemptying. Following administration of a single dose of paracetamol 1,000 mg, paracetamol AUC andt1/2 were unchanged whatever the timing of its administration (before or after the lixisenatideinjection). When administered 1 or 4 hours after 10 mcg lixisenatide, Cmax of paracetamol wasdecreased by 29% and 31% respectively and median tmax was delayed by 2.0 and 1.75 hoursrespectively. A further delay in tmax and a reduced Cmax of paracetamol have been predicted with the20 mcg maintenance dose.

No effects on paracetamol Cmax and tmax were observed when paracetamol was administered 1 hourbefore lixisenatide.

Based on these results, no dose adjustment for paracetamol is required but the delayed tmax observedwhen paracetamol is administered 1-4 hours after lixisenatide should be taken into account when arapid onset of action is required for efficacy.

Following administration of a single dose of an oral contraceptive medicinal product (ethinylestradiol0.03 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 before or 4 hours after lixisenatide did not affect AUCand 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 andmedian tmax was delayed by 1 to 3 hours.

The reduction in Cmax is of limited clinical relevance and no dose adjustment for oral contraceptives isrequired.

When lixisenatide 20 mcg and atorvastatin 40 mg were co-administered in the morning for 6 days, theexposure to atorvastatin was not affected, while Cmax was decreased by 31% and tmax was delayed by3.25 hours.

No such increase for tmax was observed when atorvastatin was administered in the evening andlixisenatide 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 requiredwhen co-administered with lixisenatide.

After concomitant administration of warfarin 25 mg with repeated dosing of lixisenatide 20 mcg, therewere no effects on AUC or INR (International Normalised Ratio) while Cmax was reduced by 19% andtmax was delayed by 7 hours.

Based on these results, no dose adjustment for warfarin is required when co-administered withlixisenatide; however, frequent monitoring of INR in patients on warfarin and/or coumarin derivativesis 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 AUCof digoxin was not affected. The tmax of digoxin was delayed by 1.5 hour and the Cmax was reduced by26%.

Based on these results, no dose adjustment for digoxin is required when co-administered withlixisenatide.

Ramipril

After concomitant administration of lixisenatide 20 mcg and ramipril 5 mg during 6 days, the AUC oframipril was increased by 21% while the Cmax was decreased by 63%. The AUC and Cmax of the activemetabolite (ramiprilat) were not affected. The tmax of ramipril and ramiprilat were delayed byapproximately 2.5 hours.

Based on these results, no dose adjustment for ramipril is required when co-administered withlixisenatide.

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 haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Lyxumiashould not be used during pregnancy. The use of insulin is recommended instead. If a patient wishes tobecome 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 duringbreast-feeding.

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

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

Over 2,600 patients have received Lyxumia either alone or in combination with metformin, asulphonylurea (with or without metformin) or a basal insulin (with or without metformin, or with orwithout a sulphonylurea) in 8 large placebo- or active-controlled phase III studies.

The most frequently reported adverse reactions during clinical studies were nausea, vomiting anddiarrhoea. These reactions were mostly mild and transient.

In addition, hypoglycaemia (when Lyxumia was used in combination with a sulphonylurea and/or abasal insulin) and headache occurred.

Allergic reactions have been reported in 0.4% of Lyxumia patients.

Adverse reactions reported from placebo- and active-controlled phase III studies over the entiretreatment period are presented in Table 1. The table presents adverse reactions that occurred with anincidence >5% if the frequency was higher among Lyxumia treated patients than patients treated withall comparators. The table also includes adverse reactions with a frequency ≥1% in the Lyxumia groupif 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 theentire treatment period (including the period beyond the main 24-week treatment period in studieswith ≥76 weeks of total treatment).

System Organ Frequency of occurrence

Class

Very common Common Uncommon Rare

Infections and Influenzainfestations Upper respiratorytract infection

Cystitis

Viral infection

Immune system Anaphylacticdisorders reaction

Metabolism and Hypoglycaemia (in Hypoglycaemia (innutrition disorders combination with a combination withsulphonylurea and/metformin alone)or a basal insulin)

Nervous system Headache Dizzinessdisorders Somnolence

Gastrointestinal Nausea Dyspepsiadisorders Vomiting Delayedgastricemptying

Hepatobiliary Cholelithiasisdisorders Cholecystitis

Skin and Urticariasubcutaneoustissue disorders

Musculoskeletal Back painand connectivetissue disorders

General disorders Injection siteand pruritusadministration siteconditions

In patients taking Lyxumia in monotherapy, symptomatic hypoglycaemia occurred in 1.7% oflixisenatide treated patients and in 1.6% of placebo treated patients. When Lyxumia is used incombination with metformin alone, symptomatic hypoglycaemia occurred in 7.0% of lixisenatidepatients and in 4.8% of placebo patients during the entire treatment period.

In patients taking Lyxumia in combination with a sulphonylurea and metformin, symptomatichypoglycaemia occurred in 22.0% of lixisenatide treated patients and in 18.4% of placebo treatedpatients during the entire treatment period (3.6% absolute difference). When Lyxumia is used incombination with a basal insulin with or without metformin, symptomatic hypoglycaemia occurred in42.1% 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, symptomatichypoglycaemia 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, symptomatichypoglycaemia 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 lixisenatidepatients and 0.2% in placebo patients) during the entire treatment period of the Phase IIIplacebo-controlled studies.

Nausea and vomiting were the most frequently reported adverse reactions during the main 24-weektreatment period. The incidence of nausea was higher in the lixisenatide group (26.1%) compared tothe 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 occurred during the first3 weeks after starting treatment. Thereafter, they progressively decreased during the following weeks.

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

Consistent with the potentially immunogenic properties of medicinal products containing proteins orpeptides, patients may develop anti-lixisenatide antibodies following treatment with Lyxumia and, atthe end of the main 24-week treatment period in placebo-controlled studies, 69.8% of lixisenatidepatients had a positive antibody status. The percentage of patients who were antibody positive wassimilar at the end of the entire 76-week treatment period. At the end of the main 24-week treatmentperiod, 32.2% of the patients having a positive antibody status had an antibody concentration abovethe lower limit of quantification, and at the end of the entire 76-week treatment period, 44.7% of thepatients had an antibody concentration above the lower limit of quantification. After stopping thetreatment, few antibody positive patients were followed-up for antibody status; the percentagedecreased 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 statusor an antibody concentration below the lower limit of quantification and the other 20.7% of patientshad a quantified antibody concentration. In the subset of patients (5.2%) with the highest antibodyconcentrations, the mean improvement in HbA1c at Week 24 and at Week 76 was in a clinicallyrelevant 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 individualpatient.

There was no difference in the overall safety profile in patients regardless of the antibody status withthe exception of an increase of the incidence of injection site reactions (4.7% in antibody positivepatients compared to 2.5% in antibody-negative patients during the entire treatment period). Themajority 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 possibly associated with lixisenatide (such as anaphylactic reaction, angioedemaand urticaria) have been reported in 0.4% of lixisenatide patients while possibly associated allergicreactions 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 theplacebo group. Most of these reported allergic reactions were mild in severity.

One case of anaphylactoid reaction was reported during clinical trials with lixisenatide.

In a study in healthy volunteers, a transient rise in heart rate has been observed after administration oflixisenatide 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.

The incidence of treatment discontinuation due to adverse events was 7.4% for Lyxumia compared to3.2% in the placebo group during the main 24-week treatment period. The most common adversereactions which led to treatment discontinuation in the lixisenatide group were nausea (3.1%) andvomiting (1.2%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

During clinical studies, doses up to 30 mcg of lixisenatide twice a day were administered to type 2diabetic patients in a 13-week study. An increased incidence of gastrointestinal disorders wasobserved.

In case of overdose, appropriate supportive treatment should be initiated according to the patient’sclinical signs and symptoms and the lixisenatide dose should be reduced to the prescribed dose.

Pharmacotherapeutic group: Drugs used in Diabetes, Glucagon-like peptide-1 (GLP-1) analogues,

ATC code: A10BJ03

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 thepancreatic beta cells.

Lixisenatide action is mediated via a specific interaction with GLP-1 receptors, leading to an increasein intracellular cyclic adenosine monophosphate (cAMP). Lixisenatide stimulates insulin secretionwhen 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 ofglucagon secretion is preserved.

Lixisenatide slows gastric emptying thereby reducing the rate at which meal-derived glucose appearsin the circulation.

When administered once daily, lixisenatide improves glycaemic control through the immediate andsustained effects of lowering both post-prandial and fasting glucose concentrations in patients withtype 2 diabetes.

This effect on post-prandial glucose was confirmed in a 4-week study versus liraglutide 1.8 mg once aday in combination with metformin. Reduction from baseline in the AUC0:30-4:30 h of plasma glucoseafter a test-meal was: -12.61 h*mmol/L (-227.25 h*mg/dl) in the lixisenatide groupand -4.04 h*mmol/L (-72.83 h*mg/dl) in the liraglutide group. This was also confirmed in an 8-weekstudy versus liraglutide, administered before breakfast, in combination with insulin glargine with orwithout metformin.

The clinical efficacy and safety of Lyxumia were evaluated in nine randomised double-blind,placebo-controlled clinical studies including 4,508 patients with type 2 diabetes (2,869 patientsrandomised to lixisenatide, 47.5% men and 52.5% women, and 517 were ≥65 years of age).

Efficacy of Lyxumia was also assessed in two randomised, open-label, active-controlled study (versusexenatide or versus insulin glulisine) and in a mealtime study (in total 1,067 patients randomised tolixisenatide).

Efficacy and safety of Lyxumia in patients older than 70 years was addressed in a specificallydedicated placebo-controlled study (176 patients randomised to lixisenatide, including 62 patients ≥75years of age).

In addition, a double-blind, placebo-controlled cardiovascular outcome study (ELIXA) enrolled 6,068type 2 diabetes patients with previous acute coronary syndrome (3,034 randomised to lixisenatide,including 198 patients ≥75 years of age and 655 patients with moderate renal impairment).

In the completed Phase III studies, it was observed that approximately 90% of the patients were able toremain on the once daily maintenance dose of 20 mcg Lyxumia at the end of the main 24-weektreatment period.

* Glycaemic control

Add-on combination therapy with oral antidiabetics

Lyxumia in combination with metformin, a sulphonylurea, pioglitazone or a combination of theseagents showed statistically significant reductions in HbA1c, in fasting plasma glucose and in 2-hourpost-prandial glucose after a test-meal compared to placebo at the end of the main 24-week treatmentperiod (tables 2 and 3). The HbA1c reduction was significant with once-daily administration, whetheradministered morning or evening.

This effect on HbA1c was sustained in long term studies for up to 76 weeks.

Add-on treatment to metformin alone

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

Metformin as background therapy

Lixisenatide Placebo Lixisenatide 20 mcg Placebo20 mcg (N= 159) (N= 170)(N= 160)

Morning Evening(N= 255) (N= 255)

Mean HbA1c (%)

Baseline 7.99 8.03 8.07 8.07 8.02

LS mean change from -0.92 -0.42 -0.87 -0.75 -0.38baseline

Patients (%) achieving HbA1c<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 -2.63 -1.63 -2.01 -2.02 -1.64baseline

In an active-controlled study, Lyxumia once daily showed an HbA1c reduction of -0.79% comparedto -0.96% with exenatide twice daily at the end of the main 24-week treatment period with a meantreatment 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 to 35.1% in the exenatidetwice daily group and the incidence of symptomatic hypoglycaemia with lixisenatide was 2.5% duringthe 24-week main treatment period compared to 7.9% in the exenatide group.

In a 24-week open-label study, lixisenatide administered before the main meal of the day wasnon-inferior to lixisenatide administered before breakfast in terms of HbA1c reduction (LS meanchange from baseline: -0.65% versus -0.74%). Similar HbA1c decreases were observed regardless ofwhich meal was the main meal (breakfast, lunch or dinner). At the end of the study, 43.6% (main mealgroup) and 42.8% (breakfast group) of patients achieved an HbA1c less than 7%. Nausea was reportedin 14.7% and 15.5% of patients, and symptomatic hypoglycaemia in 5.8% and 2.2% of patients, mainmeal group and breakfast group, respectively.

Add-on treatment to a sulphonylurea alone or in combination with metformin

Table 3: Placebo-controlled study in combination with a sulphonylurea (24-week results)

Sulphonylurea as background therapywith or without metformin

Lixisenatide 20 mcg Placebo(N= 570) (N= 286)

Mean HbA1c (%)

Baseline 8.28 8.22

LS mean change frombaseline -0.85 -0.10

Patients (%) achieving

HbA1c <7.0% 36.4 13.5

Mean body weight (kg)

Baseline 82.58 84.52

LS mean change frombaseline -1.76 -0.93

Add-on treatment to pioglitazone alone or in combination with metformin

In a clinical study, the addition of lixisenatide to pioglitazone with or without metformin, in patientsnot 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 maintreatment period. At the end of the 24-week main treatment period, 52.3% of the lixisenatide patientsachieved 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 groupcompared to 10.6% in the placebo group and symptomatic hypoglycaemia was reported in 3.4% of thelixisenatide patients compared to 1.2% in the placebo group.

Add-on combination therapy with a basal insulin

Lyxumia given with a basal insulin alone, or with a combination of a basal insulin and metformin, or acombination 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 Basal insulin as background therapytherapy Alone or in combination with a

Alone or in combination with sulphonylurea *metformin

Lixisenatide Placebo Lixisenatide Placebo20 mcg (N= 166) 20 mcg (N= 157)(N= 327) (N= 154)

Mean HbA1c (%)

Baseline 8.39 8.38 8.53 8.53

LS mean changefrom baseline -0.74 -0.38 -0.77 0.11

Patients (%)achieving HbA1c 28.3 12.0 35.6 5.2<7.0%

Mean duration oftreatment with basal 3.06 3.2 2.94 3.01insulin at baseline(years)

Mean change in basalinsulin dose (U)

Baseline 53.62 57.65 24.87 24.11

LS mean changefrom baseline -5.62 -1.93 -1.39 -0.11

Mean body weight(kg)

Baseline 87.39 89.11 65.99 65.60

LS mean changefrom baseline -1.80 -0.52 -0.38 0.06

*performed in Asian population

A clinical study was conducted in insulin-naive patients insufficiently controlled on oral antidiabeticagents. This study consisted of a 12-week run-in period with introduction and titration of insulinglargine and of a 24-week treatment period during which patients receive either lixisenatide or placeboin combination with insulin glargine and metformin with or without thiazolidinediones. Insulinglargine was continuously titrated during this period.

During the 12-week run-in period, addition and titration of insulin glargine resulted approximately inan HbA1c decrease of 1%. The addition of lixisenatide led to a significantly greater HbA1c decrease of0.71% in the lixisenatide group compared to 0.40% in the placebo group. At the end of the 24-weektreatment period, 56.3% of the lixisenatide patients achieved an HbA1c less than 7 % compared to38.5% in the placebo group.

During the 24-week treatment period, 22.4% lixisenatide patients reported at least one symptomatichypoglycaemic event compared to 13.5% in the placebo group. The incidence of hypoglycaemia wasmainly increased in the lixisenatide group during the first 6 weeks of treatment and thereafter, wassimilar to the placebo group.

Patients with type 2 diabetes with basal insulin combined with 1-3 oral anti-diabetic agents wereenrolled in an open-label randomised study for insulin intensification. After 12-week of optimalinsulin glargine titration with or without metformin, inadequately controlled patients were randomisedto add single dose of lixisenatide or a single dose (QD) of insulin glulisine (both before the largestmeal) or insulin glulisine administered three times a day (TID) for 26 weeks.

The level of HbA1c reduction was comparable between groups (table 5).

As opposed to both insulin glulisine treatment regimens, lixisenatide reduced body weight (table 5).

The rate of symptomatic hypoglycaemic events was lower with lixisenatide (36%) compared to insulinglulisine QD and TID (47% and 52%, respectively).

Table 5: Active-controlled study in combination with basal insulin with or without metformin(26-week results) - (mITT) and safety population

Lixisenatide Insulin glulisine Insulin glulisine

QD TID

Mean HbA1c (%) N = 297 N = 298 N = 295

LS change from baseline -0.63 -0.58 -0.84

LS mean difference (SE) oflixisenatide versus -0.05 (0.059) 0.21 (0.059)95% CI (-0.170 to 0.064) (0.095 to 0.328)

Mean body weight N = 297 N = 298 N = 295

LS change from baseline -0.63 +1.03 +1.37

LS mean difference (SE) oflixisenatide versus -1.66 (0.305) -1.99 (0.305)95% CI (-2.257 to -1.062) (-2.593 to -1.396)*

*p<0.0001

* Fasting plasma glucose

The reductions in fasting plasma glucose obtained with Lyxumia treatment ranged from 0.42 mmol/Lto 1.19 mmol/L (7.6 to 21.4 mg/dl) from baseline at the end of the main 24-week treatment period inplacebo-controlled studies.

* Post-prandial glucose

Treatment with Lyxumia resulted in reductions in 2-hour post-prandial glucose after a test-mealstatistically superior to placebo whatever the background treatment.

The reductions with Lyxumia ranged from 4.51 to 7.96 mmol/L (81.2 to 143.3 mg/dl) from baseline atthe end of the main 24-week treatment period across all studies in which post-prandial glucose wasmeasured; 26.2% to 46.8% of patients had a 2-hour post-prandial glucose value below 7.8 mmol/L(140.4 mg/dl).

* Body weight

Treatment with Lyxumia in combination with metformin and/or a sulphonylurea resulted in asustained body weight change from baseline in all controlled studies in a range from -1.76 kg to -2.96 kg at the end of the main 24-week treatment period.

Body weight change from baseline in a range from -0.38 kg to -1.80 kg was also observed inlixisenatide patients receiving stable basal insulin dose, alone or in combination with metformin or asulphonylurea.

In patients newly started on insulin, body weight remained almost unchanged in the lixisenatide groupwhile an increase was shown in the placebo group.

Body weight reduction was sustained in long term studies up to 76 weeks.

The body weight reduction is independent from the occurrence of nausea and vomiting.

* Beta cell function

Clinical studies with Lyxumia indicate improved beta-cell function as measured by the homeostasismodel assessment for beta-cell function (HOMA-β).

Restoration of first phase insulin secretion and improved second phase insulin secretion in response toan intravenous bolus of glucose were demonstrated in patients with type 2 diabetes (n=20) after asingle dose of Lyxumia.

* Cardiovascular evaluation

No increase in mean heart rate in patients with type 2 diabetes was seen in all placebo controlled phase

III studies.

Mean systolic and diastolic blood pressure reductions up to 2.1 mmHg and up to 1.5 mmHgrespectively were observed in phase III placebo-controlled studies.

The ELIXA study was a randomized, double-blind, placebo-controlled, multinational study thatevaluated cardiovascular (CV) outcomes during treatment with lixisenatide in patients with type 2diabetes mellitus after a recent Acute Coronary Syndrome.

Overall, 6068 patients were randomized 1:1 to either placebo or lixisenatide 20 mcg (following astarting dose of 10 mcg during the first 2 weeks).

Ninety-six percent of the patients in both treatment groups completed the study in accordance with theprotocol and the vital status was known at the end of the study for 99.0% and 98.6% of the patients inthe lixisenatide and placebo group, respectively. Median treatment duration was 22.4 months in thelixisenatide group and 23.3 months in the placebo group, and the median duration of study follow-upwas 25.8 and 25.7 months, respectively. Mean HbA1c (±SD) in the lixisenatide and placebo groupswas 7.72 (±1.32) % and 7.64 (±1.28) % at baseline and 7.46 (±1.51) % and 7.61 (±1.48) % at 24months, respectively.

The results of the primary and secondary composite efficacy endpoints, and the results of all theindividual components of the composite endpoints are shown in Figure 1.

Figure 1: Forest plot: analyses of each individual cardiovascular event -- ITT population

Lixi n(%) Placebo n(%) HR [95% CI]

Primary composite endpoint

CV death, non-fatal MI, 406 (13.4%) 399 (13.2%) 1.02 [0.89, 1.17]non-fatal stroke,or hospitalization forunstable angina

Secondary composite endpointsprimary + HF 456 (15.0%) 469 (15.5%) 0.97 [0.85, 1.10]primary + HF + Revasc 661 (21.8%) 659 (21.7%) 1.00 [0.90, 1.11]

Individual components of composites

CV death 156 (5.1%) 158 (5.2%) 0.98 [0.78, 1.22]

MI 270 (8.9%) 261 (8.6%) 1.03 [0.87, 1.23]

Stroke 67 (2.2%) 60 (2.0%) 1.12 [0.79, 1.58]

Hospitalization for 11 (0.4%) 10 (0.3%) 1.11 [0.47, 2.62]unstable angina

Hospitalization for 122 (4.0%) 127 (4.2%) 0.96 [0.75, 1.23]heart failure

Coronary revascularization 368 (12.1%) 356 (11.7%) 1.03 [0.89, 1.19]procedure0.0 0.5 1.0 1.5 2.0 2.5 3.0

Harzard Ratio with 95% CI

CV: cardiovascular, MI: myocardial infarction, HF: hospitalization for heart failure, Revasc: coronaryrevascularization procedure, HR: hazard ratio, CI: confidence interval.

People aged ≥70 years

The efficacy and safety of lixisenatide in people aged ≥70 years with type 2 diabetes was evaluated ina double-blind, placebo-controlled study of 24 weeks duration. Frail patients, including patients at riskfor malnutrition, patients with recent cardiovascular events and patients with moderate to severecognitive impairment were excluded. A total of 350 patients were randomized (randomization ratio1:1). Overall, 37% of the patients were ≥75 years old (N=131) and 31% had moderate renalimpairment (N=107). Patients received stable dose(s) of oral antidiabetic drug(s) (OAD) and/or basalinsulin as background therapy. Sulfonylureas or glinides were not used with basal insulin asbackground therapy.

Lixisenatide provided significant improvements in HbA1c (-0.64% change compared to placebo; 95%

CI: -0.810% to -0.464%; p<0.0001), from a mean baseline HbA1c of 8.0%.

The European Medicines Agency has waived the obligation to submit the results of studies with

Lyxumia in all subsets of the paediatric population in type 2 diabetes mellitus (see section 4.2 forinformation on paediatric use).

Following subcutaneous administration to patients with type 2 diabetes, the rate of lixisenatideabsorption is rapid and not influenced by the dose administered. Irrespective of the dose and whetherlixisenatide was administered as single or multiple doses, the median tmax is 1 to 3.5 hours in patientswith type 2 diabetes. There are no clinically relevant differences in the rate of absorption whenlixisenatide is administered subcutaneously in the abdomen, thigh, or arm.

Lixisenatide has a moderate level of binding (55%) to human proteins.

The apparent volume of distribution after subcutaneous administration of lixisenatide (Vz/F) isapproximately 100 L.

As a peptide, lixisenatide is eliminated through glomerular filtration, followed by tubular reabsorptionand subsequent metabolic degradation, resulting in smaller peptides and amino acids, which arereintroduced in the protein metabolism.

After multiple dose administration in patients with type 2 diabetes, mean terminal half-life wasapproximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h.

In subjects with mild (creatinine clearance calculated by the Cockcroft-Gault formula 60-90 ml/min),moderate (creatinine clearance 30-60 ml/min) and severe renal impairment (creatinine clearance15-30 ml/min), AUC was increased by 46%, 51% and 87%, respectively.

As lixisenatide is cleared primarily by the kidney, no pharmacokinetic study has been performed inpatients with acute or chronic hepatic impairment. Hepatic dysfunction is not expected to affect thepharmacokinetics of lixisenatide.

Gender has no clinically relevant effect on the pharmacokinetics of lixisenatide.

Ethnic origin had no clinically relevant effect on the pharmacokinetics of lixisenatide based on theresults of pharmacokinetic studies in Caucasian, Japanese and Chinese subjects.

Age has no clinically relevant effect on the pharmacokinetics of lixisenatide. In a pharmacokineticstudy in elderly non-diabetic subjects, administration of lixisenatide 20 mcg resulted in a meanincrease of lixisenatide AUC by 29% in the elderly population (11 subjects aged 65 to 74 years and 7subjects aged ≥75 years) compared to 18 subjects aged 18 to 45 years, likely related to reduced renalfunction in the older age group.

Body weight has no clinically relevant effect on lixisenatide AUC.

Non-clinical data reveal no special hazards for humans based on conventional studies of safetypharmacology and toxicology.

In 2-year subcutaneous carcinogenicity studies, non-lethal C-cell thyroid tumours were seen in ratsand mice and are considered to be caused by a non-genotoxic GLP-1 receptor-mediated mechanism towhich rodents are particularly sensitive. C-cell hyperplasia and adenoma were seen at all doses in ratsand a no observed adverse effect level (NOAEL) could be not defined. In mice, these effects occurredat exposure ratio above 9.3-fold when compared to human exposure at the therapeutic dose. No C-cellcarcinoma was observed in mice and C-cell carcinoma occurred in rats with an exposure ratio relativeto exposure at human therapeutic dose of about 900-fold. In 2-year subcutaneous carcinogenicity studyin mice, 3 cases of adenocarcinoma in the endometrium were seen in the mid dose group with astatistically significant increase, corresponding to an exposure ratio of 97-fold. No treatment-relatedeffect was demonstrated.

Animal studies did not indicate direct harmful effects with respect to male and female fertility in rats.

Reversible testicular and epididymal lesions were seen in dogs treated with lixisenatide. No relatedeffect on spermatogenesis was seen in healthy men.

In embryo-foetal development studies, malformations, growth retardation, ossification retardation andskeletal effects were observed in rats at all doses (5-fold exposure ratio compared to human exposure)and in rabbits at high doses (32-fold exposure ratio compared to human exposure) of lixisenatide. Inboth species, there was a slight maternal toxicity consisting of low food consumption and reducedbody weight. Neonatal growth was reduced in male rats exposed to high doses of lixisenatide duringlate gestation and lactation, with a slightly increased pup mortality observed.

Glycerol 85%

Sodium acetate trihydrate

Methionine

Metacresol

Hydrochloric acid (for pH adjustment)

Sodium hydroxide solution (for pH adjustment)

Water for injections

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

3 years.

After first use: 14 days

Store in a refrigerator (2°C - 8°C).

Do not freeze.

Store away from the freezer compartment.

After first use

Store below 30°C. Do not freeze.

Do not store with a needle attached. Keep the cap on the pen in order to protect from light.

Type I glass cartridge with a (bromobutyl) rubber plunger, flanged caps (aluminium) with insertedlaminated sealing disks (bromobutyl rubber on the inside and polyisoprene on the outside). Eachcartridge is assembled into a disposable pen.

Lyxumia 10 micrograms solution for injection

Each green pre-filled pen contains 3 ml solution, delivering 14 doses of 10 mcg.

Pack containing 1 green pre-filled pen.

Lyxumia 20 micrograms solution for injection

Each purple pre-filled pen contains 3 ml solution, delivering 14 doses of 20 mcg.

Packs containing 1, 2 and 6 purple pre-filled pens.

Not all pack sizes may be marketed.

Lyxumia should not be used if it has been frozen.

Lyxumia can be used with 29 to 32 gauge disposable pen needles. Pen needles are not included.

The patient should be instructed to discard the needle after each use in accordance with localrequirements and to store the pen without the needle attached. This helps prevent contamination andpotential needle blockage. The pen is to be used for one patient only.

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

Sanofi Winthrop Industrie82 avenue Raspail94250 Gentilly

France

Lyxumia 10 micrograms solution for injection

EU/1/12/811/001 (1 pre-filled pen)

Lyxumia 20 micrograms solution for injection

EU/1/12/811/002 (1 pre-filled pen)

EU/1/12/811/003 (2 pre-filled pens)

EU/1/12/811/004 (6 pre-filled pens)

Date of first authorisation: 01 February 2013

Date of latest renewal: 18 September 2017

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.