Lyxumia

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 

 



 

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1. NAME OF THE MEDICINAL PRODUCT 

 

Lyxumia 10 micrograms solution for injection 

Lyxumia 20 micrograms solution for injection 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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. 

 

 

3. PHARMACEUTICAL FORM 

 

Solution for injection (injection). 

Clear, colourless solution.  

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Lyxumia is indicated for the treatment of adults with type 2 diabetes mellitus to achieve glycaemic 

control 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 5.1 

for available data on the different combinations). 

 

4.2 Posology and method of administration 

 

Posology 

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 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. 

 



 

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Special populations 

Elderly  
No dose adjustment is required based on age. 

 

Patients with renal impairment 
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 less 

than 30 ml/min) or end-stage renal disease and therefore, it is not recommended to use lixisenatide in 

these populations (see section 5.2). 
 

Patients with hepatic impairment 

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

Paediatric population 

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. 
 

Method of administration 

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

 

The injection is administered once daily, within the hour prior to any meal of the day. It is preferable 
that the prandial injection of Lyxumia is performed before the same meal every day, when the most 

convenient meal has been chosen. If a dose is missed, it should be injected within the hour prior to the 

next meal.  

 

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 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. 

 
Acute pancreatitis  

Use of glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with a risk of 

developing acute pancreatitis. There have been few reported events of acute pancreatitis with 

lixisenatide although a causal relationship has not been established. 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. 
 

Severe gastrointestinal disease 

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. 

 

Renal impairment 
There is no therapeutic experience in patients with severe renal impairment (creatinine clearance less 

than 30 ml/min) or end-stage renal disease. Use is not recommended in patients with severe renal 

impairment or end-stage renal disease (see sections 4.2 and 5.2). 



 

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Hypoglycaemia 

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). Lixisenatide should not be given in combination 

with basal insulin and a sulphonylurea due to increased risk of hypoglycaemia. 
 

Concomitant medicinal products 

The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally 

administered medicinal products. Lixisenatide 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. 
 

Populations not studied 

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

 
Dehydration 

Patients treated with lixisenatide should be advised of the potential risk of dehydration in relation to 

gastrointestinal adverse reactions and take precautions to avoid fluid depletion. 
 

Excipients 

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”. 

 

4.5 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 

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 1,000 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. 

 



 

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Oral contraceptives  

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. 

 

Atorvastatin 
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. 

 

Warfarin and other coumarin derivatives 
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. 

 
Digoxin 

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. 

 
Ramipril 

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. 

 

4.6 Fertility, pregnancy and lactation 

 

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

 

Pregnancy 

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. 

 



 

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Breast-feeding 

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

breast-feeding. 

 

Fertility 

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

 

4.7 Effects on ability to drive and use machines 

 

Lixisenatide 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. 

 

4.8 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. 
 



 

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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 Dyspepsia  

Vomiting   

Diarrhoea   

   

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). 

 



 

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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 occurred 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. 



 

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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. 
 

4.9 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. 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

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

ATC code: A10BJ03  

 

Mechanism of action 

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. 

 

Pharmacodynamic effects 

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 in combination with metformin. Reduction from baseline in the AUC0:30-4:30 h of plasma glucose 

after a test-meal was: -12.61 h*mmol/L (-227.25 h*mg/dl) in the lixisenatide group 

and -4.04 h*mmol/L (-72.83 h*mg/dl) in the liraglutide group. This was also confirmed in an 8-week 

study versus liraglutide, administered before breakfast, in combination with insulin glargine with or 

without metformin. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

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Clinical efficacy and safety 

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 patients 

randomised 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 (versus 

exenatide or versus insulin glulisine) and in a meal time study (in total 1,067 patients randomised to 

lixisenatide). 

 

Efficacy and safety of Lyxumia in patients older than 70 years was addressed in a specifically 

dedicated placebo-controlled study (176 patients randomised to lixisenatide, including 62 patients ≥75 

years of age). 

 

In addition, a double-blind, placebo-controlled cardiovascular outcome study (ELIXA) enrolled 6,068 

type 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 to 
remain on the once daily maintenance dose of 20 mcg Lyxumia at the end of the main 24-week 

treatment period. 

 

• Glycaemic control 

 

Add-on combination therapy with oral antidiabetics 

  

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. 

 

Add-on treatment to metformin alone  

 

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

 

 Metformin as background therapy 

 Lixisenatide 

20 mcg  

(N= 160) 

Placebo  

(N= 159) 

Lixisenatide 20 mcg 

 

Placebo  

(N= 170) 

   Morning 

(N= 255) 

Evening 

(N= 255) 

 

Mean HbA1c (%) 

Baseline 

LS mean change from 

baseline 

 

7.99 

-0.92 

 

8.03 

-0.42 

 

8.07 

-0.87 

 

8.07 

-0.75 

 

8.02 

-0.38 

Patients (%) achieving HbA1c 

<7.0% 

 

47.4 

 

24.1 

 

43.0 

 

40.6 

 

22.0 

Mean body weight (kg) 

Baseline 

LS mean change from 

baseline 

 

90.30 

-2.63 

 

87.86 

-1.63 

 

90.14 

-2.01 

 

89.01 

-2.02 

 

90.40 

-1.64 

 



 

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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 to 35.1% 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. 

 
In a 24-week open-label study, lixisenatide administered before the main meal of the day was 

non-inferior to lixisenatide administered before breakfast in terms of HbA1c reduction (LS mean 

change from baseline: -0.65% versus -0.74%). Similar HbA1c decreases were observed regardless of 
which meal was the main meal (breakfast, lunch or dinner). At the end of the study, 43.6% (main meal 

group) and 42.8% (breakfast group) of patients achieved an HbA1c less than 7%. Nausea was reported 

in 14.7% and 15.5% of patients, and symptomatic hypoglycaemia in 5.8% and 2.2% of patients, main 

meal 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 therapy 

with or without metformin  

 Lixisenatide 20 mcg 

(N= 570) 

Placebo  

(N= 286) 

Mean HbA1c (%) 

Baseline 

LS mean change from 

baseline 

 

8.28 

 

-0.85 

 

8.22 

 

-0.10 

Patients (%) achieving 

HbA1c <7.0% 

 

36.4 

 

13.5 

Mean body weight (kg) 

Baseline 

LS mean change from 

baseline 

 

82.58 

 

-1.76 

 

84.52 

 

-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 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. 

 

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 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. 

 



 

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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= 327) 

Placebo  

(N= 166) 

Lixisenatide 

20 mcg 

(N= 154) 

Placebo  

(N= 157) 

Mean HbA1c (%) 

Baseline 

LS mean change 

from baseline 

 

8.39 

 

-0.74 

 

8.38 

 

-0.38 

 

8.53 

 

-0.77 

 

8.53 

 

0.11 

Patients (%) achieving 

HbA1c <7.0% 

 

28.3 

 

12.0 

 

35.6 

 

5.2 

Mean duration of 

treatment with basal 

insulin at baseline 

(years) 

 

3.06 

 

3.2 

 

2.94 

 

3.01 

Mean change in basal 

insulin dose (U) 

Baseline 

LS mean change 

from baseline 

 

 

53.62 

 

-5.62 

 

 

57.65 

 

-1.93 

 

 

24.87 

 

-1.39 

 

 

24.11 

 

-0.11 

Mean body weight 

(kg) 

Baseline 

LS mean change 

from baseline 

 

 

87.39 

 

-1.80 

 

 

89.11 

 

-0.52 

 

 

65.99 

 

-0.38 

 

 

65.60 

 

0.06 

*performed in Asian population 

 
A clinical study was conducted in insulin-naive patients insufficiently controlled on oral antidiabetic 

agents. This study consisted of a 12-week run-in period with introduction and titration of insulin 

glargine and of a 24-week treatment period during which patients receive either lixisenatide or placebo 
in combination with insulin glargine and metformin with or without thiazolidinediones. Insulin 

glargine was continuously titrated during this period. 

During the 12-week run-in period, addition and titration of insulin glargine resulted approximately in 

an HbA1c decrease of 1%. The addition of lixisenatide led to a significantly greater HbA1c decrease of 
0.71% in the lixisenatide group compared to 0.40% in the placebo group. At the end of the 24-week 

treatment period, 56.3% of the lixisenatide patients achieved an HbA1c less than 7 % compared to 

38.5% in the placebo group. 
During the 24-week treatment period, 22.4% lixisenatide patients reported at least one symptomatic 

hypoglycaemic event compared to 13.5% in the placebo group. The incidence of hypoglycaemia was 

mainly increased in the lixisenatide group during the first 6 weeks of treatment and thereafter, was 
similar to the placebo group. 

 

Patients with type 2 diabetes with basal insulin combined with 1-3 oral anti-diabetic agents were 
enrolled in an open-label randomised study for insulin intensification. After 12-week of optimal 

insulin glargine titration with or without metformin, inadequately controlled patients were randomised 

to add single dose of lixisenatide or a single dose (QD) of insulin glulisine (both before the largest 

meal) 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 insulin 

glulisine QD and TID (47% and 52%, respectively). 



 

13 

Table 5: Active-controlled study in combination with basal insulin with or without metformin 

(26-week results) - (mITT) and safety population 
 

 Lixisenatide  Insulin glulisine  

QD 

Insulin glulisine  

TID 

Mean HbA1c (%) 

LS change from baseline 

LS mean difference (SE) of 

lixisenatide versus 

95% CI 

N = 297 

-0.63 

N = 298 

-0.58 

 

-0.05 (0.059) 

(-0.170 to 0.064) 

N = 295 

-0.84 

 

0.21 (0.059) 

(0.095 to 0.328) 

 

Mean body weight 

 

N = 297 

 

N = 298 

 

N = 295 

LS change from baseline 

LS mean difference (SE) of 

lixisenatide versus 

95% CI 

-0.63 

 

 

 

+1.03 

 

-1.66 (0.305) 

(-2.257 to -1.062) 

+1.37 

 

-1.99 (0.305) 

(-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/L 
to 1.19 mmol/L (7.6 to 21.4 mg/dl) from baseline at the end of the main 24-week treatment period in 

placebo-controlled studies. 

 

• Post-prandial glucose 
Treatment with Lyxumia resulted in reductions in 2-hour post-prandial glucose after a test-meal 

statistically 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 at 
the end of the main 24-week treatment period across all studies in which post-prandial glucose was 

measured; 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 a 

sustained 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 in 

lixisenatide patients receiving stable basal insulin dose, alone or in combination with metformin or a 
sulphonylurea. 

In patients newly started on insulin, body weight remained almost unchanged in the lixisenatide group 

while 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 homeostasis 
model assessment for beta-cell function (HOMA-β). 

Restoration of first phase insulin secretion and improved second phase insulin secretion in response to 

an intravenous bolus of glucose were demonstrated in patients with type 2 diabetes (n=20) after a 
single dose of Lyxumia. 

 



 

14 

• 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 mmHg 

respectively were observed in phase III placebo-controlled studies. 

 
The ELIXA study was a randomized, double-blind, placebo-controlled, multinational study that 

evaluated cardiovascular (CV) outcomes during treatment with lixisenatide in patients with type 2 

diabetes mellitus after a recent Acute Coronary Syndrome. 
 

Overall, 6068 patients were randomized 1:1 to either placebo or lixisenatide 20 mcg (following a 

starting 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 the 

protocol and the vital status was known at the end of the study for 99.0% and 98.6% of the patients in 

the lixisenatide and placebo group, respectively. Median treatment duration was 22.4 months in the 
lixisenatide group and 23.3 months in the placebo group, and the median duration of study follow-up 

was 25.8 and 25.7 months, respectively. Mean HbA1c (±SD) in the lixisenatide and placebo groups 

was 7.72 (±1.32)% and 7.64 (±1.28)% at baseline and 7.46 (±1.51)% and 7.61 (±1.48)% at 24 months, 
respectively. 

 

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

 

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

 

Harzard Ratio with 95% CI

0.0 0.5 1.0 1.5 2.0 2.5 3.0

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 for
      unstable angina

Secondary composite endpoints

      primary + 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]
      procedure

 

CV: cardiovascular, MI: myocardial infarction, HF: hospitalization for heart failure, Revasc: coronary 

revascularization procedure, HR: hazard ratio, CI: confidence interval. 



 

15 

Elderly 

People aged ≥70 years 

The efficacy and safety of lixisenatide in people aged ≥70 years with type 2 diabetes was evaluated in 

a double-blind, placebo-controlled study of 24 weeks duration. Frail patients, including patients at risk 
for malnutrition, patients with recent cardiovascular events and patients with moderate to severe 

cognitive impairment were excluded. A total of 350 patients were randomized (randomization ratio 

1:1). Overall, 37% of the patients were ≥75 years old (N=131) and 31% had moderate renal 
impairment (N=107). Patients received stable dose(s) of oral antidiabetic drug(s) (OAD) and/or basal 

insulin as background therapy. Sulfonylureas or glinides were not used with basal insulin as 

background 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%. 

 

Paediatric population 

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

Lyxumia in one or more subsets of the paediatric population in type 2 diabetes mellitus (see 
section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

Following subcutaneous administration to patients with type 2 diabetes, the rate of lixisenatide 

absorption is rapid and not influenced by the dose administered. Irrespective of the dose and whether 

lixisenatide was administered as single or multiple doses, the median tmax is 1 to 3.5 hours in patients 

with type 2 diabetes. There are no clinically relevant differences in the rate of absorption when 

lixisenatide is administered subcutaneously in the abdomen, thigh, or arm. 

 

Distribution 

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

The apparent volume of distribution after subcutaneous administration of lixisenatide (Vz/F) is 

approximately 100 L. 

 

Biotransformation and elimination 

As a peptide, lixisenatide is eliminated through glomerular filtration, followed by tubular reabsorption 

and subsequent metabolic degradation, resulting in smaller peptides and amino acids, which are 

reintroduced in the protein metabolism. 

 

After multiple dose administration in patients with type 2 diabetes, mean terminal half-life was 

approximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h. 

 

Special populations 

Patients with renal impairment 

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 clearance 

15-30 ml/min), AUC was increased by 46%, 51% and 87%, respectively. 

 

Patients with hepatic impairment 

As lixisenatide is cleared primarily by the kidney, no pharmacokinetic study has been performed in 

patients with acute or chronic hepatic impairment. Hepatic dysfunction is not expected to affect the 

pharmacokinetics of lixisenatide.  

 

Gender 

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

 



 

16 

Race 

Ethnic origin had no clinically relevant effect on the pharmacokinetics of lixisenatide based on the 

results of pharmacokinetic studies in Caucasian, Japanese and Chinese subjects.  

 

Elderly 

Age has no clinically relevant effect on the pharmacokinetics of lixisenatide. In a pharmacokinetic 

study in elderly non-diabetic subjects, administration of lixisenatide 20 mcg resulted in a mean 

increase of lixisenatide AUC by 29% in the elderly population (11 subjects aged 65 to 74 years and 7 

subjects aged ≥75 years) compared to 18 subjects aged 18 to 45 years, likely related to reduced renal 

function in the older age group. 

 

Body weight 

Body weight has no clinically relevant effect on lixisenatide AUC.  

 

5.3 Preclinical safety data 

 

Non-clinical data reveal no special hazards for humans based on conventional studies of safety 

pharmacology and toxicology. 

 

In 2-year subcutaneous carcinogenicity studies, non-lethal C-cell thyroid tumours were seen in rats 

and mice and are considered to be caused by a non-genotoxic GLP-1 receptor-mediated mechanism to 

which rodents are particularly sensitive. C-cell hyperplasia and adenoma were seen at all doses in rats 

and a no observed adverse effect level (NOAEL) could be not defined. In mice, these effects occurred 

at exposure ratio above 9.3-fold when compared to human exposure at the therapeutic dose. No C-cell 

carcinoma was observed in mice and C-cell carcinoma occurred in rats with an exposure ratio relative 

to exposure at human therapeutic dose of about 900-fold. In 2-year subcutaneous carcinogenicity study 

in mice, 3 cases of adenocarcinoma in the endometrium were seen in the mid dose group with a 

statistically significant increase, corresponding to an exposure ratio of 97-fold. No treatment-related 

effect 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 related 

effect on spermatogenesis was seen in healthy men. 

In embryo-foetal development studies, malformations, growth retardation, ossification retardation and 

skeletal 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. In 

both species, there was a slight maternal toxicity consisting of low food consumption and reduced 

body weight. Neonatal growth was reduced in male rats exposed to high doses of lixisenatide during 

late gestation and lactation, with a slightly increased pup mortality observed. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Glycerol 85% 

Sodium acetate trihydrate 

Methionine 

Metacresol 

Hydrochloric acid (for pH adjustment) 

Sodium hydroxide solution (for pH adjustment) 

Water for injections 

 



 

17 

6.2 Incompatibilities 

 

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

products. 

 

6.3 Shelf life 

 

2 years. 

 

After first use: 14 days 

 

6.4 Special precautions for storage 

 

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. 

 

6.5 Nature and contents of container 

 

Type I glass cartridge with a (bromobutyl) rubber plunger, flanged caps (aluminium) with inserted 

laminated sealing disks (bromobutyl rubber on the inside and polyisoprene on the outside). Each 

cartridge 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. 

 

6.6 Special precautions for disposal and other handling 

 

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 local 

requirements and to store the pen without the needle attached. This helps prevent contamination and 

potential 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 local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

sanofi-aventis groupe 

54, rue La Boétie 
F – 75008 Paris 

France 

 



 

18 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

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) 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 01 February 2013 

Date of latest renewal: 

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

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

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

 



 

19 

1. NAME OF THE MEDICINAL PRODUCT 

 

Treatment initiation pack 

Lyxumia 10 micrograms solution for injection 

Lyxumia 20 micrograms solution for injection 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

 

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. 

 

 

3. PHARMACEUTICAL FORM 

 

Solution for injection (injection). 

Clear, colourless solution.  

 

 

4. CLINICAL PARTICULARS 

 

4.1 Therapeutic indications 

 

Lyxumia is indicated for the treatment of adults with type 2 diabetes mellitus to achieve glycaemic 

control 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 5.1 

for available data on the different combinations). 

 

4.2 Posology and method of administration 

 

Posology 

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.   

 
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. 

 
Special populations 

Elderly  

No dose adjustment is required based on age. 

 



 

20 

Patients with renal impairment 

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 less 

than 30 ml/min) or end-stage renal disease and therefore, it is not recommended to use lixisenatide in 

these populations (see section 5.2). 
 

Patients with hepatic impairment 

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

 
Paediatric population 

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. 
 

Method of administration  

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

 

The injection is administered once daily, within the hour prior to any meal of the day. It is preferable 
that the prandial injection of Lyxumia is performed before the same meal every day, when the most 

convenient meal has been chosen. If a dose is missed, it should be injected within the hour prior to the 

next meal. 

 

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 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. 

 

Acute pancreatitis  
Use of glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with a risk of 

developing acute pancreatitis. There have been few reported events of acute pancreatitis with 

lixisenatide although a causal relationship has not been established. 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. 

 
Severe gastrointestinal disease 

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. 

 

Renal impairment 

There is no therapeutic experience in patients with severe renal impairment (creatinine clearance less 
than 30 ml/min) or end-stage renal disease. Use is not recommended in patients with severe renal 

impairment or end-stage renal disease (see sections 4.2 and 5.2). 

 
Hypoglycaemia 

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). Lixisenatide should not be given in combination 

with basal insulin and a sulphonylurea due to increased risk of hypoglycaemia. 



 

21 

Concomitant medicinal products 

The delay of gastric emptying with lixisenatide may reduce the rate of absorption of orally 
administered medicinal products. Lixisenatide 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. 

 

Populations not studied 

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

Dehydration 

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

 

Excipients 

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”. 

 

4.5 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 

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 1,000 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. 

 
Oral contraceptives 

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. 



 

22 

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

required.  
 

Atorvastatin 

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. 
 

Warfarin and other coumarin derivatives 

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. 

 

Digoxin 
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. 

 

Ramipril 
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. 

 

4.6 Fertility, pregnancy and lactation 

 

Women of childbearing potential 

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

 

Pregnancy 

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.  

 

Breast-feeding 

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

 

Fertility 

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



 

23 

4.7 Effects on ability to drive and use machines 

 

Lixisenatide 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. 

 

4.8 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. 



 

24 

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 Dyspepsia  

Vomiting   

Diarrhoea   

   

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). 



 

25 

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 occurred 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. 



 

26 

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. 
 

4.9 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. 

 

 

5. PHARMACOLOGICAL PROPERTIES 

 

5.1  Pharmacodynamic properties 

 

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

ATC code: A10BJ03. 

 

Mechanism of action 

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. 

 

Pharmacodynamic effects 

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 in combination with metformin. Reduction from baseline in the AUC0:30-4:30 h of plasma glucose 

after a test meal was: -12.61 h*mmol/L (-227.25 h*mg/dl) in the lixisenatide group 

and -4.04 h*mmol/L (-72.83 h*mg/dl) in the liraglutide group. This was also confirmed in an 8-week 

study versus liraglutide, administered before breakfast, in combination with insulin glargine with or 

without metformin. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

27 

Clinical efficacy and safety 

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 patients 

randomised 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 (versus 

exenatide or versus insulin glulisine) and in a meal time study (in total 1,067 patients randomised to 

lixisenatide). 

 

Efficacy and safety of Lyxumia in patients older than 70 years was addressed in a specifically 

dedicated placebo-controlled study (176 patients randomised to lixisenatide, including 62 patients ≥75 

years of age). 

 

In addition, a double-blind, placebo-controlled cardiovascular outcome study (ELIXA) enrolled 6,068 

type 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 to 
remain on the once daily maintenance dose of 20 mcg Lyxumia at the end of the main 24-week 

treatment period. 

 

• Glycaemic control 

 

Add-on combination therapy with oral antidiabetics 

  

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. 

 

Add-on treatment to metformin alone  

 

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

 

 Metformin as background therapy 

 Lixisenatide 

20 mcg  

(N= 160) 

Placebo  

(N= 159) 

Lixisenatide 20 mcg 

 

Placebo  

(N= 170) 

   Morning 

(N= 255) 

Evening 

(N= 255) 

 

Mean HbA1c (%) 

Baseline 

LS mean change from baseline 

 

7.99 

-0.92 

 

8.03 

-0.42 

 

8.07 

-0.87 

 

8.07 

-0.75 

 

8.02 

-0.38 

Patients (%) achieving HbA1c 

<7.0% 

 

47.4 

 

24.1 

 

43.0 

 

40.6 

 

22.0 

Mean body weight (kg) 

Baseline 

LS mean change from baseline 

 

90.30 

-2.63 

 

87.86 

-1.63 

 

90.14 

-2.01 

 

89.01 

-2.02 

 

90.40 

-1.64 

 

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%). 



 

28 

The incidence of nausea was 24.5% in the lixisenatide group compared to 35.1% 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. 

 

In a 24-week open-label study, lixisenatide administered before the main meal of the day was 
non-inferior to lixisenatide administered before breakfast in terms of HbA1c reduction (LS mean 

change from baseline: -0.65% versus -0.74%). Similar HbA1c decreases were observed regardless of 

which meal was the main meal (breakfast, lunch or dinner). At the end of the study, 43.6% (main meal 
group) and 42.8% (breakfast group) of patients achieved an HbA1c less than 7%. Nausea was reported 

in 14.7% and 15.5% of patients, and symptomatic hypoglycaemia in 5.8% and 2.2% of patients, main 

meal 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 therapy 

with or without metformin  

 Lixisenatide 20 mcg 

(N= 570) 

Placebo  

(N= 286) 

Mean HbA1c (%) 

Baseline 

LS mean change from 

baseline 

 

8.28 

 

-0.85 

 

8.22 

 

-0.10 

Patients (%) achieving 

HbA1c <7.0% 

 

36.4 

 

13.5 

Mean body weight (kg) 

Baseline 

LS mean change from 

baseline 

 

82.58 

 

-1.76 

 

84.52 

 

-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 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. 

 

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 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.  



 

29 

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= 327) 

Placebo  

(N= 166) 

Lixisenatide 

20 mcg 

(N= 154) 

Placebo  

(N= 157) 

Mean HbA1c (%) 

Baseline 

LS mean change 

from baseline 

 

8.39 

 

-0.74 

 

8.38 

 

-0.38 

 

8.53 

 

-0.77 

 

8.53 

 

0.11 

Patients (%) achieving 

HbA1c <7.0% 

 

28.3 

 

12.0 

 

35.6 

 

5.2 

Mean duration of 

treatment with basal 

insulin at baseline 

(years) 

 

3.06 

 

3.2 

 

2.94 

 

3.01 

Mean change in basal 

insulin dose (U) 

Baseline 

LS mean change 

from baseline 

 

 

53.62 

 

-5.62 

 

 

57.65 

 

-1.93 

 

 

24.87 

 

-1.39 

 

 

24.11 

 

-0.11 

Mean body weight 

(kg) 

Baseline 

LS mean change 

from baseline 

 

 

87.39 

 

-1.80 

 

 

89.11 

 

-0.52 

 

 

65.99 

 

-0.38 

 

 

65.60 

 

0.06 

*performed in Asian population 

 
A clinical study was conducted in insulin-naive patients insufficiently controlled on oral antidiabetic 

agents. This study consisted of a 12-week run-in period with introduction and titration of insulin 

glargine and of a 24-week treatment period during which patients receive either lixisenatide or placebo 
in combination with insulin glargine and metformin with or without thiazolidinediones. Insulin 

glargine was continuously titrated during this period. 

During the 12-week run-in period, addition and titration of insulin glargine resulted approximately in 

an HbA1c decrease of 1%. The addition of lixisenatide led to a significantly greater HbA1c decrease of 
0.71% in the lixisenatide group compared to 0.40% in the placebo group. At the end of the 24-week 

treatment period, 56.3% of the lixisenatide patients achieved an HbA1c less than 7 % compared to 

38.5% in the placebo group. 
During the 24-week treatment period, 22.4% lixisenatide patients reported at least one symptomatic 

hypoglycaemic event compared to 13.5% in the placebo group. The incidence of hypoglycaemia was 

mainly increased in the lixisenatide group during the first 6 weeks of treatment and thereafter, was 
similar to the placebo group. 

 

Patients with type 2 diabetes with basal insulin combined with 1-3 oral anti-diabetic agents were 

enrolled in an open-label randomised study for insulin intensification. After 12-week of optimal 

insulin glargine titration with or without metformin, inadequately controlled patients were randomised 
to add single dose of lixisenatide or a single dose (QD) of insulin glulisine (both before the largest 

meal) 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 insulin 
glulisine QD and TID (47% and 52%, respectively).  



 

30 

Table 5: Active-controlled study in combination with basal insulin with or without metformin 

(26-week results) - (mITT) and safety population 
 

 Lixisenatide  Insulin glulisine  

QD 

Insulin glulisine  

TID 

Mean HbA1c (%) 

LS change from baseline 

LS mean difference (SE) of 

lixisenatide versus 

95% CI 

N = 297 

-0.63 

N = 298 

-0.58 

 

-0.05 (0.059) 

(-0.170 to 0.064) 

N = 295 

-0.84 

 

0.21 (0.059) 

(0.095 to 0.328) 

 

Mean body weight 

 

N = 297 

 

N = 298 

 

N = 295 

LS change from baseline 

LS mean difference (SE) of 

lixisenatide versus 

95% CI 

-0.63 

 

 

 

+1.03 

 

-1.66 (0.305) 

(-2.257 to -1.062) 

+1.37 

 

-1.99 (0.305) 

(-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/L 

to 1.19 mmol/L (7.6 to 21.4 mg/dl) from baseline at the end of the main 24-week treatment period in 

placebo-controlled studies. 
 

• Post-prandial glucose 
Treatment with Lyxumia resulted in reductions in 2-hour post-prandial glucose after a test-meal 

statistically 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 at 

the end of the main 24-week treatment period across all studies in which post-prandial glucose was 

measured; 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 a 
sustained 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-weeks treatment period. 

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

sulphonylurea. 

In patients newly started on insulin, body weight remained almost unchanged in the lixisenatide group 
while 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 homeostasis 

model assessment for beta-cell function (HOMA-β). 

Restoration of first phase insulin secretion and improved second phase insulin secretion in response to 
an intravenous bolus of glucose were demonstrated in patients with type 2 diabetes (n=20) after a 

single dose of Lyxumia. 

 

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

III studies. 



 

31 

Mean systolic and diastolic blood pressure reductions up to 2.1 mmHg and up to 1.5 mmHg 

respectively were observed in phase III placebo-controlled studies. 
 

The ELIXA study was a randomized, double-blind, placebo-controlled, multinational study that 

evaluated cardiovascular (CV) outcomes during treatment with lixisenatide in patients with type 2 
diabetes mellitus after a recent Acute Coronary Syndrome. 

 

Overall, 6068 patients were randomized 1:1 to either placebo or lixisenatide 20 mcg (following a 
starting 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 the 

protocol and the vital status was known at the end of the study for 99.0% and 98.6% of the patients in 
the lixisenatide and placebo group, respectively. Median treatment duration was 22.4 months in the 

lixisenatide group and 23.3 months in the placebo group, and the median duration of study follow-up 

was 25.8 and 25.7 months, respectively. Mean HbA1c (±SD) in the lixisenatide and placebo groups 
was 7.72 (±1.32)% and 7.64 (±1.28)% at baseline and 7.46 (±1.51)% and 7.61 (±1.48)% at 24 months, 

respectively. 

 
The results of the primary and secondary composite efficacy endpoints and the results of all the 

individual components of the composite endpoints are shown in Figure 1. 

 

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

 

Harzard Ratio with 95% CI

0.0 0.5 1.0 1.5 2.0 2.5 3.0

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 for
      unstable angina

Secondary composite endpoints

      primary + 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]
      procedure

 
CV: cardiovascular, MI: myocardial infarction, HF: hospitalization for heart failure, Revasc: coronary 

revascularization procedure, HR: hazard ratio, CI: confidence interval. 

 

Elderly 

People aged ≥70 years 
The efficacy and safety of lixisenatide in people aged ≥70 years with type 2 diabetes was evaluated in 

a double-blind, placebo-controlled study of 24 weeks duration. Frail patients, including patients at risk 

for malnutrition, patients with recent cardiovascular events and patients with moderate to severe 
cognitive impairment were excluded. A total of 350 patients were randomized (randomization ratio 

1:1). Overall, 37% of the patients were ≥75 years old (N=131) and 31% had moderate renal 

impairment (N=107). Patients received stable dose(s) of oral antidiabetic drug(s) (OAD) and/or basal 



 

32 

insulin as background therapy. Sulfonylureas or glinides were not used with basal insulin as 

background 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%. 

 

Paediatric population 

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

Lyxumia in one or more subsets of the paediatric population in type 2 diabetes mellitus (see 
section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 

 

Absorption 

Following subcutaneous administration to patients with type 2 diabetes, the rate of lixisenatide 

absorption is rapid and not influenced by the dose administered. Irrespective of the dose and whether 

lixisenatide was administered as single or multiple doses, the median tmax is 1 to 3.5 hours in patients 

with type 2 diabetes. There are no clinically relevant differences in the rate of absorption when 

lixisenatide is administered subcutaneously in the abdomen, thigh, or arm. 

 

Distribution 

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

The apparent volume of distribution after subcutaneous administration of lixisenatide (Vz/F) is 

approximately 100 L.  

 

Biotransformation and elimination 

As a peptide, lixisenatide is eliminated through glomerular filtration, followed by tubular reabsorption 

and subsequent metabolic degradation, resulting in smaller peptides and amino acids, which are 

reintroduced in the protein metabolism.  

 

After multiple dose administration in patients with type 2 diabetes, mean terminal half-life was 

approximately 3 hours and the mean apparent clearance (CL/F) about 35 L/h. 

 

Special populations 

Patients with renal impairment 

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 clearance 15-

30 ml/min) AUC was increased by 46%, 51% and 87%, respectively. 

 

Patients with hepatic impairment 

As lixisenatide is cleared primarily by the kidney, no pharmacokinetic study has been performed in 

patients with acute or chronic hepatic impairment. Hepatic dysfunction is not expected to affect the 

pharmacokinetics of lixisenatide. 

 

Gender 

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

 

Race 

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

 

Elderly  

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

In a pharmacokinetic study in elderly non diabetic subjects, administration of lixisenatide 20 mcg 

resulted in a mean increase of lixisenatide AUC by 29% in the elderly population (11 subjects aged 65 



 

33 

to 74 years and 7 subjects aged ≥75 years) compared to 18 subjects aged 18 to 45 years, likely related 

to reduced renal function in the older age group. 

 

Body weight 

Body weight has no clinically relevant effect on lixisenatide AUC. 

 

5.3 Preclinical safety data 

 

Non-clinical data reveal no special hazards for humans based on conventional studies of safety 

pharmacology and toxicology. 

 

In 2-year subcutaneous carcinogenicity studies, non-lethal C-cell thyroid tumours were seen in rats 

and mice and are considered to be caused by a non-genotoxic GLP-1 receptor-mediated mechanism to 

which rodents are particularly sensitive. C-cell hyperplasia and adenoma were seen at all doses in rats 

and a no observed adverse effect level (NOAEL) could be not defined. In mice, these effects occurred 

at exposure ratio above 9.3-fold when compared to human exposure at the therapeutic dose. No C-cell 

carcinoma was observed in mice and C-cell carcinoma occurred in rats with an exposure ratio relative 

to exposure at human therapeutic dose of about 900-fold. In 2-year subcutaneous carcinogenicity study 

in mice, 3 cases of adenocarcinoma in the endometrium were seen in the mid dose group with a 

statistically significant increase, corresponding to an exposure ratio of 97-fold. No treatment-related 

effect 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 related 

effect on spermatogenesis was seen in healthy men. 

In embryo-foetal development studies, malformations, growth retardation, ossification retardation and 

skeletal 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. In 

both species, there was a slight maternal toxicity consisting of low food consumption and reduced 

body weight. Neonatal growth was reduced in male rats exposed to high doses of lixisenatide during 

late gestation and lactation, with a slightly increased pup mortality observed. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Glycerol 85% 

Sodium acetate trihydrate 

Methionine 

Metacresol 

Hydrochloric acid (for pH adjustment) 

Sodium hydroxide solution (for pH adjustment) 

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 

 

2 years. 

 

After first use: 14 days 



 

34 

6.4 Special precautions for storage 

 

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. 

 

6.5 Nature and contents of container  

 

Treatment initiation pack 

Type I glass cartridge with a (bromobutyl) rubber plunger, flanged caps (aluminium) with inserted 

laminated sealing disks (bromobutyl rubber on the inside and polyisoprene on the outside).  Each 

cartridge is assembled into a disposable pen. 

 

Pack containing 1 green pre-filled pen of Lyxumia 10 micrograms solution for injection and 1 purple 

pre-filled pen of Lyxumia 20 micrograms solution for injection. 

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

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

 

6.6 Special precautions for disposal and other handling 

 

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 local 

requirements and to store the pen without the needle attached. This helps prevent contamination and 

potential 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 local 

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 

 

sanofi-aventis groupe 

54, rue La Boétie 

F – 75008 Paris 
France 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/12/811/005 (1 pre-filled pen + 1 pre-filled pen) 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 01 February 2013 

Date of latest renewal: 



 

35 

10. DATE OF REVISION OF THE TEXT 

 

 

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

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



 

36 

 

 

 
 

 

 
 

 

 
 

 

 
 

 

 
 

 

 
 

 

ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 

BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



 

37 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer of the biological active substance 

 
Sanofi-Aventis Deutschland GmbH 

Brüningstrasse 50, Industriepark Höchst 

65926 Frankfurt am Main 
Germany 

 

Name and address of the manufacturer responsible for batch release 
 

Sanofi-Aventis Deutschland GmbH 

Brüningstrasse 50, Industriepark Höchst 
65926 Frankfurt am Main 

Germany 

 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to medical prescription. 
 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

 AUTHORISATION  

 

• Periodic safety update reports 

 

The requirements for submission of periodic safety update reports for this medicinal product are 

set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of 

Directive 2001/83/EC and any subsequent updates published on the European medicines web-

portal. 

 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

• Risk Management Plan (RMP) 

 

The MAH shall perform the required pharmacovigilance activities and interventions detailed in 

the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed 

subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency; 

• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



 

38 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



 

39 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 

 



 

40 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON (INITIATION PACK) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Lyxumia 10 micrograms solution for injection 

Lixisenatide 
 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

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

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: glycerol 85%, sodium acetate trihydrate, methionine, metacresol (see leaflet for further 

information), hydrochloric acid and sodium hydroxide solution (for pH adjustment), water for 

injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 
Solution for injection 

 

1 pre-filled pen of 3 ml (14 doses) 

 
 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 
Subcutaneous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 
 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 
 

8. EXPIRY DATE 

 

EXP 

Discard pen 14 days after first use 

 

 



 

41 

9. SPECIAL STORAGE CONDITIONS 

 

Before first use 
Store in a refrigerator. Do not freeze. Store away from the freezer compartment. 

 

After first use 
Store below 30°C. Do not freeze. 

Keep the cap on the pen in order to protect from light. 

Do not store with a needle attached. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

sanofi-aventis groupe 

54, rue La Boétie 
F – 75008 Paris 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/811/001 - 1 pen 

 
 

13. BATCH NUMBER 

 

BN 
 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 
 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lyxumia 10 
 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 
 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  



 

42 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON (MAINTENANCE PACK) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 
Lyxumia 20 micrograms solution for injection 

Lixisenatide 

 
 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

3. LIST OF EXCIPIENTS 

 

Excipients: glycerol 85%, sodium acetate trihydrate, methionine, metacresol (see leaflet for further 

information), hydrochloric acid and sodium hydroxide solution (for pH adjustment), water for 

injections. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

 
1 pre-filled pen of 3 ml (14 doses) 

2 pre-filled pens of 3 ml (2x14 doses) 

6 pre-filled pens of 3 ml (6x14 doses) 
 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 
Read the package leaflet before use.  

Subcutaneous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 
 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 
EXP 

Discard pen 14 days after first use 

 

 



 

43 

9. SPECIAL STORAGE CONDITIONS 

 

Before first use 
Store in a refrigerator. Do not freeze. Store away from the freezer compartment. 

 

After first use 
Store below 30°C. Do not freeze. 

Keep the cap on the pen in order to protect from light. 

Do not store with a needle attached. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

sanofi-aventis groupe 

54, rue La Boétie 
F – 75008 Paris 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/811/002 - 1  pen 

EU/1/12/811/003 - 2 pens 
EU/1/12/811/004 - 6 pens 

 

 

13. BATCH NUMBER 

 

BN 

 
 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lyxumia 20 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 



 

44 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 



 

45 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON (28 DAYS TREATMENT INITIATION PACK) 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 
Lyxumia 10 micrograms solution for injection 

Lyxumia 20 micrograms solution for injection 

Lixisenatide 
 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 
Each dose (0.2 ml) contains 10 or 20 micrograms lixisenatide. 

 

 

3. LIST OF EXCIPIENTS 

 

Excipients: glycerol 85%, sodium acetate trihydrate, methionine, metacresol (see leaflet for further 

information), hydrochloric acid and sodium hydroxide solution (for pH adjustment), water for 

injections. 

 
 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Solution for injection 

 

Treatment initiation pack 

Each pack of 2 pre-filled pens for a 4 week treatment schedule contains: 

1 pre-filled pen of 3 ml for 14 doses of 10 micrograms 

1 pre-filled pen of 3 ml for 14 doses of 20 micrograms 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Subcutaneous use 

 

Printed on the inside:  

Read the Instructions for Use carefully before using your Lyxumia pen. 

You must start your treatment with the green pen of Lyxumia 10 micrograms. 

 
 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 
Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 



 

46 

 

8. EXPIRY DATE 

 

EXP 

Discard pen 14 days after first use 

 
 

9. SPECIAL STORAGE CONDITIONS 

 

Before first use 
Store in a refrigerator. Do not freeze. Store away from the freezer compartment. 

 

After first use 
Store below 30°C. Do not freeze. 

Keep the cap on the pen in order to protect from light.  

Do not store with a needle attached. 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

sanofi-aventis groupe 

54, rue La Boétie 
F – 75008 Paris 

France 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/12/811/005 - 2 pens 

 
 

13. BATCH NUMBER 

 

BN 
 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 
 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Lyxumia  
10 

20 

 

 



 

47 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 
2D barcode carrying the unique identifier included. 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC:  

SN:  

NN:  

 



 

48 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

PEN LABEL  

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 
Lyxumia 10 mcg injection 

Lixisenatide 

Subcutaneous use  
 

 

2. METHOD OF ADMINISTRATION 

 
 

3. EXPIRY DATE 

 

EXP 
 

 

4. BATCH NUMBER 

 
BN 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

3 ml (14 doses) 

 
 

6. OTHER  



 

49 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

PEN LABEL  

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 
Lyxumia 20 mcg injection 

Lixisenatide 

Subcutaneous use  
 

 

2. METHOD OF ADMINISTRATION 

 
 

3. EXPIRY DATE 

 

EXP 
 

 

4. BATCH NUMBER 

 
BN 

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

3 ml (14 doses) 

 
 

6. OTHER  

 



 

50 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 

 

 
 



 

51 

 

Package leaflet: Information for the user 
 

Lyxumia 10 micrograms solution for injection  

Lyxumia 20 micrograms solution for injection  

lixisenatide 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again.  
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours.  

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 

side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 

 

1. What Lyxumia is and what it is used for 
2. What you need to know before you use Lyxumia  

3. How to use Lyxumia 

4. Possible side effects 
5. How to store Lyxumia  

6. Contents of the pack and other information 

 
 

1. What Lyxumia is and what it is used for 

 

Lyxumia contains the active substance lixisenatide. 
It is an injectable medicine used to help your body to control your blood sugar level when it is too 

high. It is used in adults with type 2 diabetes. 

 
Lyxumia is used with other medicines for diabetes when they are not enough to control your blood 

sugar levels.These may include: 

• oral antidiabetics (such as metformin, pioglitazone, sulphonylurea medicines) and/ or ,  

• a basal insulin, a type of insulin which works all day. 
 

2. What you need to know before you use Lyxumia  

 
Do not use Lyxumia 

- if you are allergic to lixisenatide or any of the other ingredients of this medicine (listed in 

section 6).  
 

Warnings and precautions 

Talk to your doctor, pharmacist or nurse before using Lyxumia if: 

 
- you have type 1 diabetes or diabetic ketoacidosis (a complication of diabetes that occurs when 

the body is unable to break down glucose because there is not enough insulin) since this 

medicine will not be right for you 
 

- you have or have had inflammation of the pancreas (pancreatitis)  

 
- you have a severe stomach or gut problem such as a disease of the muscles of the stomach 

called “gastroparesis” which results in delayed stomach emptying 

 

- you have severe kidney disease or you are on dialysis as the use of this medicine will not be 
recommended  



 

52 

- you are also taking a sulphonylurea or a basal insulin. This is because low blood sugar 

(hypoglycaemia) can occur. Your doctor may want to control your blood sugar level and then, 
decide to reduce your dose of basal insulin or sulphonylurea. Lyxumia should not be used with a 

combination of both basal insulin and sulphonylurea 

 
- you are taking other medicines, as there are other medicines such as antibiotics or stomach 

resistant tablets or capsules that should not stay too long in your stomach (see section Other 

medicines and Lyxumia) 

 
- you experience loss of fluids/dehydration,e.g. in case of vomiting, nausea and diarrhoea. It is 

important to avoid dehydration by drinking plenty of fluids, especially when starting treatment 

with Lyxumia 
 

- you suffer from heart problems which can cause shortness of breath or ankle swelling, since 
there is limited experience in this population. 
 

Children and adolescents 

There is no experience with Lyxumia in children and adolescents less than 18 years and therefore, the 
use of Lyxumia is not recommended in this age group. 

 

Other medicines and Lyxumia 

Tell your doctor, pharmacist or nurse if you are using, have recently used or might use any other 
medicines. 

The effect of some medicines you swallow might be affected by Lyxumia. Some medicines such as 

antibiotics or stomach resistant tablets or capsules that should not stay too long in your stomach may 
need to be taken at least one hour before or four hours after your Lyxumia injection.  

 

Pregnancy and breast-feeding 

Lyxumia should not be used during pregnancy. It is not known if Lyxumia may harm your unborn 

child.  

Lyxumia should not be used if breast-feeding. It is not known if Lyxumia passes into your milk.  

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 

 

Driving and using machines 
If you use Lyxumia with a sulphonylurea or a basal insulin, you may get low blood sugar 

(hypoglycaemia). This may make it difficult to concentrate and you may feel dizzy or sleepy. If this 

happens do not drive or use any tools or machines. 

 
Important information about some of the ingredients of Lyxumia 

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

This medicine contains metacresol which may cause allergic reactions. 
 

 

3. How to use Lyxumia 

 

Always use this medicine exactly as your doctor, pharmacist or nurse has told you. Check with your 

doctor, pharmacist or nurse if you are not sure.  
 

How much to inject 

• The starting dose is 10 micrograms once a day for the first 14 days – injected using the green 
pen.  

• The dose from then onwards will be 20 micrograms once a day -using the purple pen. 
 



 

53 

When to inject 

Inject Lyxumia in the hour before any meal of the day. Preferably inject Lyxumia before the same 
meal every day, when you have chosen the most convenient meal for your injection. 

 

Where to inject 

Inject Lyxumia into the skin (subcutaneously) of your stomach area (abdomen), upper leg (thigh) or 

upper arm. 

 
Learning how to use the pre-filled pens 

Before you use the pen for the first time, your doctor or nurse will show how to inject Lyxumia. 

 

• Always read the "Instructions for Use" provided in the box. 

• Always use the pen as described in the “Instructions for Use”.  

 

Other important information about using the pre-filled pens 

There is more information on how to use the pens in the “Instructions for Use”. The most important 

points are: 

• Always use a new needle for each injection. You must dispose of the needle after each use, in an 

appropriate sharp’s container, following local recommendations. Speak to your doctor, nurse or 

pharmacist about how to dispose of sharps. 

• Only use needles that are compatible for use with Lyxumia pen (see “Instructions for Use”). 

• You must activate your Lyxumia pen before you use it for the first time. This is to make 
sure that it is working correctly and that the dose for your first injection is correct.  

• If you think your Lyxumia pen may be damaged, do not use it. Get a new one. Do not try to 

repair the pen. 

 
If you use more Lyxumia than you should 

If you use more Lyxumia than you should, talk to your doctor immediately. Too much Lyxumia can 

make you feel sick or be sick. 

 
If you forget to use Lyxumia 

If you miss a dose of Lyxumia, you can inject it in the hour before your next meal. Do not take two 

doses at the same time to make up for a forgotten injection. 
 

If you stop using Lyxumia 

Do not stop using Lyxumia without talking with your doctor. If you stop using Lyxumia, your blood 
sugar levels can increase. 

 

If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist. 

 
 

4. Possible side effects 

 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 

 

Some severe allergic reactions (such as anaphylaxis) have been reported uncommonly in patients 
receiving Lyxumia. You should seek immediate medical attention if you experience symptoms like 

swelling of the face, tongue or throat which causes difficulty with breathing.  

 

Stop taking Lyxumia and contact a doctor immediately if you notice any of the following serious side 

effects:  

• Severe and persistent pain in the abdomen (stomach area) which might reach through to your 
back, as well as nausea and vomiting, as it could be a sign of an inflamed pancreas 
(pancreatitis). 



 

54 

The most frequent side effects reported with Lyxumia that may affect more than 1 in 10 users 

(frequency very common) were nausea (feeling sick) and vomiting. These side effects were mostly 
mild and usually go away over time. 

 

Other side effects include 
Very common side effects: may affect more than 1 in 10 people 

• Diarrhoea 

• Headache 

• Low blood sugar (hypoglycaemia (“hypo”) especially when Lyxumia is used with insulin or a 
sulphonylurea  

The warning signs of low blood sugar may include cold sweat, cool pale skin, headache, feeling 

drowsy, weak, dizzy, confused or irritable, feeling hungry, fast heart beat and feeling jittery. Your 
doctor will tell you what to do if you get a low blood sugar. 

This is more likely to happen if you also take a sulphonylurea or a basal insulin.Your doctor may 

reduce your dose of these medicines before you start using Lyxumia. 
 

Common side effects: may affect up to 1 in 10 people 

• Flu (influenza) 

• Cold (upper respiratory tract infection) 

• Feeling dizzy 

• Indigestion (dyspepsia) 

• Back pain 

• Cystitis 

• Viral infection 

• Low blood sugar (when Lyxumia is taken with metformin) 

• Drowsiness (somnolence) 

• Injection site reactions (such as itching). 
 
Uncommon side effect: may affect up to 1 in 100 people 

• Hives (urticaria) 
 

Reporting of side effects 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 
 

 

5. How to store Lyxumia 

 

Keep this medicine out of the sight and reach of children. 

Do not use this medicine after the expiry date which is stated on the pen label and on the carton after 

EXP. The expiry date refers to the last day of the month. 
 

Before first use  

Store in a refrigerator (2°C-8°C). Do not freeze. Keep away from the freezer compartment. 
 

During use of the pen 

The pen can be used for 14 days when stored at a temperature below 30°C. Do not freeze. Do not store 

with a needle attached. When you are not using the pen, keep the cap  on the pen in order to protect 

from light. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


 

55 

6. Contents of the pack and other information 

 
What Lyxumia contains  

- The active substance is lixisenatide. 
- Lyxumia 10 micrograms solution for injection: Each dose contains 10 micrograms of 

lixisenatide (50 micrograms per ml). 

- Lyxumia 20 micrograms solution for injection: Each dose contains 20 micrograms of 
lixisenatide (100 micrograms per ml).  

- The other ingredients are glycerol 85 %, sodium acetate trihydrate, methionine, metacresol, 
hydrochloric acid (for pH adjustment), sodium hydroxide solution (for pH adjustment) and 

water for injections. 

 
What Lyxumia looks like and contents of the pack 

Lyxumia is a clear and colourless solution for injection (injection) filled in a glass cartridge inserted in 

a pre-filled pen. 

 
Each green pen of Lyxumia 10 micrograms solution for injection contains 3 ml of solution , delivering 

14 doses of 10 micrograms. Pack size of 1 pre-filled pen. 

 
Each purple pen of Lyxumia 20 micrograms solution for injection contains 3 ml of solution , 

delivering 14 doses of 20 micrograms. Pack sizes of 1, 2 or 6 pre-filled pens. Not all pack sizes may 

be available in your country. 
 

A treatment initiation pack is also available for use during the first 28 days of treatment. The treatment 

initiation pack contains one green pen of Lyxumia 10 micrograms solution for injection and one 

purple pen of Lyxumia 20 micrograms solution for injection. 
 

Marketing Authorisation Holder 

sanofi-aventis groupe  
54, rue La Boétie 

F – 75008 Paris 

France 
 

Manufacturer 

Sanofi-Aventis Deutschland GmbH 

Industriepark Höchst - 65926 Frankfurt am Main 
Germany 

 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 

 

België/Belgique/Belgien 

Sanofi Belgium 

Tél/Tel: +32 (0)2 710 54 00 

 

Lietuva 

UAB “SANOFI-AVENTIS LIETUVA”  

Tel: +370 5 2755224 

 

България 

sanofi-aventis Bulgaria EOOD 

Тел.: +359 (0)2 970 53 00 

 

Luxembourg/Luxemburg 

Sanofi Belgium  

Tél/Tel: +32 (0)2 710 54 00 (Belgique/Belgien) 

 
Česká republika 

sanofi-aventis, s.r.o. 

Tel: +420 233 086 111 

 

Magyarország 

SANOFI-AVENTIS Zrt. 

Tel.: +36 1 505 0050 

 
Danmark 

Sanofi A/S 

Tlf: +45 45 16 70 00 
 

Malta 

Sanofi S.p.A. 

Tel: +39 02 39394275 
 



 

56 

Deutschland 

Sanofi-Aventis Deutschland GmbH 

Tel: +49 (0)180 2 222010 

 

Nederland 

sanofi-aventis Netherlands B.V. 

Tel: +31 20 245 4000 

 
Eesti 

sanofi-aventis Estonia OÜ 

Tel: +372 627 34 88 
 

Norge 

sanofi-aventis Norge AS 

Tlf: +47 67 10 71 00 
 

Ελλάδα 

sanofi-aventis AEBE 
Τηλ: +30 210 900 16 00 

 

Österreich 

sanofi-aventis GmbH 
Tel: +43 1 80 185 – 0 

 

España 

sanofi-aventis, S.A 
Tel: +34 93 485 94 00 

 

Polska 

sanofi-aventis Sp. z o.o. 
Tel.: +48 22 280 00 00 

 

France 

sanofi-aventis France 

Tél: 0 800 222 555 

Appel depuis l’étranger : +33 1 57 63 23 23 
 

Portugal 

Sanofi - Produtos Farmacêuticos, Lda. 

Tel: +351 21 35 89 400 

 

Hrvatska 

sanofi-aventis Croatia d.o.o. 

Tel: +385 1 600 34 00 
 

România 

Sanofi Romania SRL 

Tel: +40 (0) 21 317 31 36 
 

Ireland 

sanofi-aventis Ireland Ltd. T/A SANOFI 
Tel: +353 (0) 1 403 56 00 

 

Slovenija 

sanofi-aventis d.o.o. 
Tel: +386 1 560 48 00 

 

Ísland 

Vistor hf. 
Sími: +354 535 7000 

 

Slovenská republika 

sanofi-aventis Pharma Slovakia s.r.o. 
Tel: +421 2 33 100 100 

 

Italia 

Sanofi S.p.A. 

Tel: 800 13 12 12 (domande di tipo tecnico)  

800 536389 (altre domande) 

 

Suomi/Finland 

Sanofi Oy 

Puh/Tel: +358 (0) 201 200 300 

 

Κύπρος 

sanofi-aventis Cyprus Ltd. 

Τηλ: +357 22 871600 

 

Sverige 

Sanofi AB 

Tel: +46 (0)8 634 50 00 

 
Latvija 

sanofi-aventis Latvia SIA 

Tel: +371 67 33 24 51 

 

United Kingdom 

Sanofi 

Tel: +44 (0) 845 372 7101 

 
 

This leaflet was last revised in 

 
Detailed information on this medicine is available on the European Medicines Agency web site: 

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



 

57 

 

Lyxumia 10 micrograms solution for injection 

 

Lixisenatide 

 

INSTRUCTIONS FOR USE 

 

Each pre-filled pen contains 14 doses, each dose contains 10 micrograms in 0.2 ml. 

 

Section 1 - IMPORTANT INFORMATION 

 

Read these instructions carefully before using your Lyxumia pen. 

Keep this leaflet for future reference 

 

Lyxumia pen Information 

 

Lyxumia comes as a pre-filled pen for injection.   

• Only inject one dose per day. 

• Each Lyxumia pen contains 14 pre-set doses. There is no need to measure each dose.   

• Talk with your doctor, pharmacist or nurse about how to inject correctly before using it. 

• If you cannot follow all the instructions completely on your own, or are not able to handle the pen 
(for example, if you have vision problems), only use it if you have help. 

 

About Your Lyxumia Pen 

 

 

 

 
 

 

 

 

 

Black plunger 

The plunger will move along the dose 

scale after each injection. 

In the example above, the dose number 

shows there are 13 injections left. 

 

• This pen is only for one person. Do not share it with anyone else. 

• Always check the label to ensure you have the correct Lyxumia pen. Also, check it has not passed 
the expiry date. Using the wrong medicine could be harmful to your health. 

• Do not try to take liquid out of the cartridge using a syringe. 
 

Activation 

window 

Injection 

button 

Arrow 
window 

Dose scale 
Cartridge 

Pen cap 

Rubber seal 



 

58 

About your needle (supplied separately) 

 

 

 

 

 

 

 

 

 

 

• Only use needles that are approved for use with Lyxumia. Use 29 to 32 gauge disposable pen 
needles with your Lyxumia pen. Ask your doctor, pharmacist or nurse which needle gauge and 
length is best for you. 

• If another person is giving the injection, they should take care not to injure anyone accidentally 
with the needle. This could possibly pass on infection. 

• Always use a new needle for each injection. This helps prevent contamination of Lyxumia or 
possible needle blockage. 

 

 

Section 2 - GETTING STARTED 

• Activate the pen on the same day as your first injection 
 

First activate your new pen 

• Before injecting a dose - before injecting you must first remove excess liquid from your new 
pen. This is done once and is called the ‘activation’ process. Steps 1 to 5 below show you how to 

do this. 

• Activation is done to make sure that the pen is working correctly and that the dose for your first 
injection is correct.  

• Do not repeat the activation process or you will not obtain 14 doses from your Lyxumia pen. 

The pictures below show how the activation window on the injection button of your pen changes after 

activation. 

 

New pen  

(orange window) 

 

 

 

 

 

 

 

 

Pen ready for injections  

(white window) 

 

 

The pen is activated and ready for injections. The window remains white after activation. 

 

 

Outer 

needle cap 

Inner 

needle 

cap 

Needle Protective 

seal 



 

59 

How to activate your new Lyxumia pen 

 

 

Step 1 Pull off the pen cap and check the pen 
 

 

 
Check the liquid. It should be clear and colourless with no 

particles. If not, do not use this pen. 

Contact your doctor, pharmacist or nurse. 

 Check that the 

activation window 

is orange. 

 

Step 2 Attach a needle and remove the needle caps 

 

 
Always use a new needle for activation.  

Remove the protective seal from the outer needle cap 
Line up the needle with the pen. Keep it straight as you screw it on. 

 

 

 
 
Take care not to injure yourself when the needle is exposed. 

Pull off the outer and inner needle caps. Keep the outer needle cap - you will need it to remove the 

needle later. 
 

 

 
Step 3 Pull injection button out 

 

 
Pull the injection button out firmly until it stops.  

 

 

The arrow will now be pointing towards the needle. 
 

 

Step 4 Press and hold injection button to remove excess liquid  

 

Keep Discard 



 

60 

 
Point the needle into a suitable container (like a paper cup or tissue) to capture the liquid so that it can 

be thrown away. 

Press the injection button all the way in.  You may feel or hear a “click”. 

Keep the injection button pressed in and slowly count to 5 in order to expel the last drops. 

 

If no liquid comes out see the “Questions and answers” section.  

Check that the activation window is now white. 
 

Step 5 The pen is now activated 

Do not activate this pen again. 

 

You do not need to replace the needle between activation and your first injection. 

For your first injection go directly to Section 3 – Step C. 

 

Turn over 

 

Section 3 - DAILY USE OF PEN  

 

Only follow this section when the activation window is white. 

Inject only one dose each day. 

 

 

 

Click 

secs 



 

61 

Step A. Pull off the pen cap and check the pen 

 

 
Check the liquid. It should be clear and colourless with no particles. If not, do not use this pen. In case 
of air bubbles see the “Questions and answers” section. 

 

Check the number of doses in the pen. This is shown by the placement of the black plunger in the dose 

scale. 
 

Check that the activation window is white. If it is orange, go to Section 2. 

Check the label on your pen to make sure you have the correct medicine.  

Step B. Attach a new needle and remove the needle caps 

 

 
Always use a new needle for each injection. 

Remove protective seal from the outer needle cap. 
Line up the needle with the pen. Keep it straight as you screw it on. 

 

 

 
 

Take care not to injure yourself when the needle is exposed. 
 

Pull off the outer and inner needle caps. Keep the outer needle cap - you will need it to remove the 

needle later. 

 

 

Step C. Pull the injection button out 

 

 
Pull the injection button out firmly until it stops. 

 

 

The arrow will now be pointing towards the needle. 
 

 

Keep Discard 



 

62 

Step D. Press and hold the injection button to inject the dose 

 

 

 
 
Grasp a fold of skin and insert the needle (see the “Injection sites” section about where to inject). 

 

Press the injection button all the way in.  You may feel or hear a “click”. 

 
Keep the injection button pressed in and slowly count to 5 to get the full dose. 

 

Your dose has now been given. Pull the needle out of your skin. 
 

 

Step E. Remove and throw away the needle after each injection 
 

 
 
Put the outer needle cap on a flat surface. Guide the needle into the outer needle cap. 

Put the outer needle cap back on. 

 

 
 

 

Squeeze the outer needle cap to grip the needle and use it to unscrew the needle from the pen. 

 

 

 

 

 

 

 

Ask your pharmacist how to throw away the needle you no longer use. 

Replace the pen cap 

 



 

63 

Step F. Repeat all steps in Section 3 for each injection. 

Throw away a pen 14 days after activation. Do this even if there is some medicine left in the pen. 

 

Table of activation and disposal 

In the table, write the date when you activated your pen and the date to throw it away 14 days later. 

 

Pen Date of 

activation 

Date to 

discard 

1   

 

Storage 

 

General information 

• Keep your Lyxumia pens in a safe place out of the reach and sight of children. 

• Protect your Lyxumia pens from dust and dirt.  

• Replace the pen cap after each use in order to protect from light. 

• Do not use Lyxumia after the expiry date which is stated on the label and on the carton. The 
expiry date refers to the last day of that month. 

 

Before activation of the pen: 

• Store your unused Lyxumia pens in the refrigerator, 2°C to 8°C.  

• Do not freeze Lyxumia pens and do not use Lyxumia if it has been frozen. 

• Allow your pen to warm at room temperature before using. 
 

After activation of the pen: 

• Once activated, store your Lyxumia pen below 30°C. Do not freeze Lyxumia once it has been 
activated. 

• Do not store your Lyxumia pen with the needle attached. An attached needle might lead to 
contamination and possible intake of air which might impact the dose accuracy. 

• Once your Lyxumia pen is activated it can be used for up to 14 days. Throw away a used 
Lyxumia pen after 14 days. Do this even if there is some medicine left in the pen. 

 

 

Disposal 

• Replace the pen cap before you throw away your Lyxumia pen.  

• Throw away your Lyxumia pen, ask your pharmacist how to throw away medicines you no longer 
use. 

 

 

Maintenance 

• Handle your Lyxumia pen with care. 

• You can clean the outside of your Lyxumia pen by wiping it with a damp cloth. 

• Do not soak, wash or put liquid on (lubricate) your Lyxumia pen, this may damage it. 

• If you think your Lyxumia pen may be damaged, do not use it. Do not try to repair the pen. 
 



 

64 

Injection sites 

 

 
 
Lyxumia must be injected under the skin and can be injected in any of the areas shown above in blue. 

These are the thigh, abdomen or upper arm. Ask your doctor, pharmacist or nurse about how to inject 

correctly. 
 

 

 

Questions and answers 

 

What if I forget to activate the Lyxumia pen or inject myself before activation? 

If you have injected yourself before activating the pen, do not correct this by giving yourself a second 

injection. Contact your doctor, pharmacist or nurse for advice on checking your blood sugar. 

 

What if there are air bubbles in the container? 

Small air bubbles in the container are normal - they will not harm you. Your dose will be correct and 

you can keep following the instructions. Contact your doctor, pharmacist or nurse if you need help. 

 

What if no liquid comes out during activation? 

The needle may be blocked or not properly screwed on. Remove the needle from the pen, attach a new 

one and repeat Steps 4 and 5 only. If still no liquid comes out, your Lyxumia pen may be damaged. Do 

not use this Lyxumia pack. Contact your doctor, pharmacist or nurse for help. 

 

What if it is hard to press the injection button all the way in? 

The needle may be blocked or not properly screwed on. Pull the needle out of your skin and remove 

the needle from the pen. Attach a new needle and repeat Steps D and E only. If it is still hard to press 

the injection button, your Lyxumia pen may be damaged. Do not use this Lyxumia pack. Contact your 

doctor, pharmacist or nurse for help. 

 

If you have any questions about Lyxumia or about diabetes, ask your doctor, pharmacist or nurse or 

call the local sanofi-aventis number in the Lyxumia “Package leaflet: Information for the user” 

(provided separately in the box). 

 

Back Front 



 

65 

 

 

Lyxumia 20 micrograms solution for injection 

 

Lixisenatide 

 

INSTRUCTIONS FOR USE 

 

Each pre-filled pen contains 14 doses, each dose contains 20 micrograms in 0.2 ml. 

 

 

Section 1 - IMPORTANT INFORMATION 

 

Read these instructions carefully before using your Lyxumia pen. 

Keep this leaflet for future reference 

 

Lyxumia pen Information 

 

Lyxumia comes as a pre-filled pen for injection. 

• Only inject one dose per day. 

• Each Lyxumia pen contains 14 pre-set doses. There is no need to measure each dose. 

• Talk with your doctor, pharmacist or nurse about how to inject correctly before using it. 

• If you cannot follow all the instructions completely on your own, or are not able to handle the pen 
(for example, if you have vision problems), only use it if you have help. 

 

About Your Lyxumia pen 

 

 

 
 

 

 

 

Black plunger 
The plunger will move along 

the dose scale after each 

injection. In the example above 
the dose number shows there 

are 13 injections left 

 

• This pen is only for one person. Do not share it with anyone else. 

• Always check the label to ensure you have the correct Lyxumia pen. Also, check it has not passed 
the expiry date. Using the wrong medicine could be harmful to your health. 

 

Activation 

window 

Injection 

button 

Arrow 

window 

Dose scale Pen cap 

Rubber seal 

Cartridge 



 

66 

• Do not try to take liquid out of the cartridge using a syringe. 
 

About your needle (supplied separately) 

 

 

 

 

 

 

 

 

 

• Only use needles that are approved for use with Lyxumia. Use 29 to 32 gauge disposable pen 
needles with your Lyxumia pen. Ask your doctor, pharmacist or nurse which needle gauge and 
length is best for you. 

• If another person is giving the injection, they should take care not to injure anyone accidentally 
with the needle. This could possibly pass on infection. 

• Always use a new needle for each injection. This helps prevent contamination of Lyxumia or 
possible needle blockage. 

 
 

Section 2 - GETTING STARTED 

 

• Activate the pen on the same day as your first injection. 
 

First activate your new pen 

• Before injecting a dose - before injecting you must first remove excess liquid from your new 
pen. This is done once and is called the ‘activation’ process. Steps 1 to 5 below show you how to 

do this. 

• Activation is done to make sure that the pen is working correctly and that the dose for your first 
injection is correct. 

• Do not repeat the activation process or you will not obtain 14 doses from your Lyxumia pen. 
 

The pictures below show how the activation window on the injection button of your pen changes after 

activation. 

 

 

New pen  

 (orange window) 

 
 

Pen ready for injections  

(white window) 

 
 

 

 

 

The pen is activated and ready for injections. The window remains white after activation. 

 

 

Outer 

needle cap 

Inner 

needle cap 
Needle Protective 

seal 



 

67 

 
 

How to activate your new Lyxumia pen 

Step 1 Pull off the pen cap and check the pen 

 

 

 

 
Check the liquid. It should be clear and colourless and 

with no particles. If not, do not use this pen. 

Contact your doctor, pharmacist or nurse. 

 Check that the activation 

window is orange 

 
 

Step 2 Attach a needle and remove the needle caps 

 

 
 
Always use a new needle for activation. 

Remove the protective seal from the outer needle cap. 

Line up the needle with the pen. Keep it straight as you screw it on. 
 

 

 
 

Take care not to injure yourself when the needle is exposed. 
Pull off the outer and inner needle caps. Keep the outer needle cap – you will need it to remove the 

needle later. 

 
 

Step 3 Pull injection button out 

 

 
Pull the injection button out firmly until it stops.  
 

 

 
The arrow will now be pointing towards the needle. 
 

Keep Discard 



 

68 

Step 4 Press and hold the injection button to remove excess liquid 

 

 
 

Point the needle into a suitable container (like a paper cup or tissue) to capture the liquid so that it can 
be thrown away. 

Press the injection button all the way in.  You may feel or hear a “click”. 

Keep the injection button pressed in and slowly count to 5 in order to expel the last drops. 

 

If no liquid comes out see the “Questions and answers” section. 

Check that the activation window is now white. 

 

 
Step 5 The pen is now activated. 

 

Do not activate this pen again. 

You do not need to replace the needle between activation and your first injection. 

For your first injection go directly to Section 3 - Step C. 

 
 

Turn over 

 

Section 3 - DAILY USE OF PEN  

 

Only follow this section when the activation window is white. 

Inject only one dose each day. 

 

 

 

Click 

secs 



 

69 

Step A. Pull off the pen cap and check the pen 

 
 

 
Check the liquid. It should be clear and colourless with no particles. If not, do not use this pen. 

In case of air bubbles see the “Questions and answers” section. 

Check the number of doses in the pen. This is shown by the placement of the black plunger in the dose 

scale. 
Check that the activation window is white.  If it is orange, go to Section 2. 

Check the label on your pen to make sure you have the correct medicine. 

 

 

Step B. Attach a new needle and remove the needle caps 

 

 
Always use a new needle for each injection. 
Remove the protective seal from the outer needle cap. 

Line up the needle with the pen. Keep it straight as you screw it on. 

 

 
 

Take care not to injure yourself when the needle is exposed. 

 

Pull off the outer and inner needle caps. Keep the outer needle cap – you will need it to remove the 
needle later. 

 

 

Step C. Pull the injection button  

 

 
Pull the injection button out firmly until it stops. 

 

 
The arrow will now be pointing towards the needle. 

 

Keep Discard 



 

70 

Step D. Press and hold the injection button to inject the dose 

 

 

 
 

Grasp a fold of skin and insert the needle (see the “Injection sites” section about where to inject).  
 

Press the injection button all the way in.  You may feel or hear a “click”. 

 
Keep the injection button pressed in and slowly count to 5 to get the full dose. 

 

Your dose has now been given. Pull the needle out of your skin. 
 

 

Step E. Remove and throw away needle after each injection 

 

 
 

Put the outer needle cap on a flat surface. Guide the needle into the outer needle cap. 
Put the outer needle cap back on. 

 

 
 

 

Squeeze the outer needle cap to grip the needle and use it to unscrew the needle from the pen. 

 

 

 

 

 

 

 

 

Ask your pharmacist how to throw away the needle you no longer use. 

Replace the pen cap. 

 

Step F. Repeat all steps in Section 3 for each injection.  

Throw away a pen 14 days after activation. Do this even if there is some medicine left in the pen. 



 

71 

Table of activation and disposal 

In the table, write the date when you activated your pen and the date to throw it away 14 days later. 

 

Pen Date of 

activation 

Date to 

discard 

1   

2   

3   

4   

5   

6   

 

 

Storage 

 

General information 

• Keep your Lyxumia pens in a safe place out of the reach and sight of children. 

• Protect your Lyxumia pens from dust and dirt.   

• Replace the pen cap after each use in order to protect from light. 

• Do not use Lyxumia after the expiry date which is stated on the label and on the carton. The 
expiry date refers to the last day of that month. 

 

Before activation of the pen: 

• Store your unused Lyxumia pens in the refrigerator, 2°C to 8°C.  

• Do not freeze Lyxumia pens and do not use Lyxumia if it has been frozen. 

• Allow your pen to warm at room temperature before using.  
 

After activation of the pen: 

• Once activated, store your Lyxumia pen below 30°C. Do not freeze Lyxumia once it has been 
activated. 

• Do not store your Lyxumia pen with the needle attached. An attached needle might lead to 
contamination and possible intake of air which might impact the dose accuracy. 

• Once your Lyxumia pen is activated it can be used for up to 14 days.  Throw away a used 
Lyxumia pen after 14 days. Do this even if there is some medicine left in the pen. 

 

Disposal 

 

• Replace the pen cap before you throw away your Lyxumia pen.  

• Throw away your Lyxumia pen, ask your pharmacist how to throw away medicines you no longer 
use. 

 

Maintenance 

• Handle your Lyxumia pen with care. 

• You can clean the outside of your Lyxumia pen by wiping it with a damp cloth. 

• Do not soak, wash or put liquid on (lubricate) your Lyxumia pen, this may damage it. 

• If you think your Lyxumia pen may be damaged, do not use it. Do not try to repair the pen. 
 



 

72 

Injection sites 

 

  
 
Lyxumia must be injected under the skin and can be injected in any of the areas shown above in blue. 

These are the thigh, abdomen or upper arm. Ask your doctor, pharmacist or nurse about how to inject 

correctly. 

 

 

 

 

Questions and answers 

 

What if I forget to activate the Lyxumia pen or inject myself before activation? 

If you have injected yourself before activating the pen, do not correct this by giving yourself a second 

injection. Contact your doctor, pharmacist or nurse for advice on checking your blood sugar. 

 

What if there are air bubbles in the container? 

Small air bubbles in the container are normal - they will not harm you. Your dose will be correct and 

you can keep following the instructions. Contact your doctor, pharmacist or nurse if you need help. 

 

What if no liquid comes out during activation? 

The needle may be blocked or not properly screwed on. Remove the needle from the pen, attach a new 

one and repeat Steps 4 and 5 only. If still no liquid comes out, your Lyxumia pen may be damaged. Do 

not use this Lyxumia pack. Contact your doctor, pharmacist or nurse for help. 

 

What if it is hard to press the injection button all the way in? 

The needle may be blocked or not properly screwed on. Pull the needle out of your skin and remove 

the needle from the pen. Attach a new needle and repeat Steps D and E only. If it is still hard to press 

the injection button, your Lyxumia pen may be damaged. Do not use this Lyxumia pack. Contact your 

doctor, pharmacist or nurse for help. 

 

If you have any questions about Lyxumia or about diabetes, ask your doctor, pharmacist or nurse or 

call the local sanofi-aventis number in the Lyxumia “Package leaflet: Information for the user” 

(provided separately in the box). 

 

 

 

Back Front 



 

73 

 

Lyxumia 

 

Lixisenatide 

INSTRUCTIONS FOR USE 

 

Treatment Initiation pack - Contains two pre-filled pens each with 14 doses. 

One green 10 microgram pen (Lyxumia 10 micrograms solution for injection), each dose contains 

10 micrograms in 0.2 ml. 

One purple 20 microgram pen (Lyxumia 20 micrograms solution for injection), each dose contains 

20 micrograms in 0.2 ml. 

 

 

Section 1 - IMPORTANT INFORMATION 

 

Read these instructions carefully before using your Lyxumia pens. 

Keep this leaflet for future reference. 

 

Lyxumia pen Information 

• Only inject one dose per day. 

• Each Lyxumia pen contains 14 pre-set doses. There is no need to measure each dose.   

• Talk with your doctor, pharmacist or nurse about how to inject correctly before using it. 

• If you cannot follow all the instructions completely on your own, or are not able to handle the pen 
(for example, if you have vision problems), only use it if you have help. 

 

About Your Treatment Initiation pack 

The Lyxumia Treatment Initiation pack includes two different coloured pens. Each pen contains a 

different strength of Lyxumia. Both pens are used in the same way. 

 

• The green pen contains 14 pre-set doses; each dose contains 10 micrograms of Lyxumia. 

• The purple pen contains 14 pre-set doses; each dose contains 20 micrograms of Lyxumia. 
You must start your treatment with the green 10 micrograms Lyxumia pen. You must first use all 

14 doses from this pen. Then use the purple 20 micrograms Lyxumia pen. 

 



 

74 

 

About Your Lyxumia pens 

Green 10 microgram Lyxumia pen 
 

 

 
 
 

 

 

Purple 20 microgram Lyxumia pen 

 

 
 

 

Black plunger 

The plunger will advance along the dose 

scale after each injection. 

In the example above, the dose number 

shows there are 13 injections left. 

 

• These pens are only for one person. Do not share them with anyone else. 

• Always check the label to ensure you have the correct Lyxumia pen. Also check it has not passed 
the expiry date. Using the wrong medicine could be harmful to your health. 

• Do not try to take liquid out of the cartridge using a syringe. 
 

About your needle (supplied separately) 
 

 

 

 

 

 

 

 

 

 

• Only use needles that are approved for use with Lyxumia. Use 29 to 32 gauge disposable pen 
needles with your Lyxumia pen. Ask your doctor, pharmacist or nurse which needle gauge and 

length is best for you. 

• If another person is giving the injection, they should take care not to injure anyone accidentally 
with the needle. This could possibly pass on infection. 

Activation 

window 

Injection 

button 

Arrow 

window 

Dose scale Cartridge Pen cap 

Rubber seal 

Outer 

needle cap 

Inner 

needle 
cap 

Needle 
Protective 

seal 



 

75 

• Always use a new needle for each injection. This helps prevent contamination of Lyxumia or 
possible needle blockage. 

 
 

Section 2 – GETTING STARTED 

 

Begin with the green 10 microgram Lyxumia pen. 

• Do not activate the purple 20 microgram Lyxumia pen until you have finished the green 
pen. 

• Activate the pen on the same day as your first injection. 

First activate your new pen 

• Before injecting a dose - before injecting you must first remove excess liquid from your new 
pen. This is done once and is called the ‘activation’ process. Steps 1 to 5 below show you how to 

do this. 

• Activation is done to make sure that the pen is working correctly and that the dose for your first 
injection is correct.  

• Do not repeat the activation process or you will not obtain 14 doses from your Lyxumia pen. 

The pictures below show how the activation window on the injection button of your pen changes after 

activation. 

 

 
New pen  

 (orange window) 

 

 

 

 

 

 

 

 

Pen ready for injections  

(white window) 

 

 

The pen is activated and ready for injections. The window remains white after activation. 

 

 

 

 

How to activate your new Lyxumia pen 

Step 1 Pull off the pen cap and check the pen 

 

 
Check the liquid.  It should be clear and colourless  
with no particles. If not, do not use this  

Treatment Initiation pack. 

Contact your doctor, pharmacist or nurse. 

 Check that the 
activation window is 

orange. 

 

 



 

76 

Step 2 Attach a needle and remove the needle caps 

 

  
 

Always use a new needle for activation. 

Remove the protective seal from the outer needle cap. 

Line up the needle with the pen. Keep it straight as you screw it on. 

 

 
 

Take care not to injure yourself when the needle is exposed. 

Pull off the outer and inner needle caps. Keep the outer needle cap – you will need it to remove the 
needle later. 

 

 

Step 3 Pull the injection button out 

 

 
Pull the injection button out firmly until it stops.  
 

 

The arrow will now be pointing towards the needle. 

 

 
Step 4 Press and hold the injection button to remove excess liquid 

 

 

 
 

Point the needle into a suitable container (like a paper cup or tissue) to capture the liquid so that it can 
be thrown away. 

Press the injection button all the way in.  You may feel or hear a “click”. 

Keep the injection button pressed in and slowly count to 5 in order to expel the last drops. 

 

Keep Discard 



 

77 

 

If no liquid comes out see the “Questions and answers” section. 
Check that the activation window is now white. 

 

 

 

Step 5 The pen is now activated. 

 

 
Do not activate this pen again. 

You do not need to replace the needle between activation and your first injection. 

For your first injection go directly to Section 3 – Step C. 

 

Turn over 

 

 

Section 3 - DAILY USE OF PEN  

 

Only follow this section when the activation window is white. 

Inject only one dose each day.  

 

 

Step A. Pull off the pen cap and check the pen  

 

 
 

Check the liquid.  It should be clear and colourless with no particles. If not, do not use this Treatment 
Initiation pack. 

In case of air bubbles see the “Questions and answers” section. 

Check the number of doses in the pen. This is shown by the placement of the black plunger in the dose 

scale. 
Check that the activation window is white.  If it is orange, go to Section 2. 

Check the label on your pen to make sure you have the correct medicine.  

 

secs 

Click 



 

78 

Step B. Attach a new needle and remove the needle caps 

 

 
 

Always use a new needle for each injection. 

Remove the protective seal from the outer needle cap 

Line up the needle with the pen. Keep it straight as you screw on. 
 

 

 

 
 

 
Take care not to injure yourself when the needle is exposed. 

Pull off the outer and inner needle caps. Keep the outer needle cap – you will need it to remove the 

needle later. 

 

Step C. Pull the injection button out 
 

 

 
Pull the injection button out firmly until it stops.  

 

 

The arrow will now be pointing towards the needle. 

 

 

Step D. Press and hold the injection button to inject the dose 
 

 

 

 

 
 

Keep Discard 



 

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Grasp a fold of skin and insert the needle (see the “Injection sites” section about where to inject).  

 
  

Press the injection button all the way in.  You may feel or hear a “click”. 

 
Keep the injection button pressed in and slowly count to 5 to get the full dose. 

 

Your dose has now been given. Pull the needle out of your skin 

 
 

 

 

Step E. Remove and throw away the needle after each injection 

 

 
 

Put the outer needle cap on a flat surface. Guide the needle into the outer needle cap. 

Put the outer needle cap back on. 
 

 
 
 

Squeeze the outer needle cap to grip the needle and use it to unscrew the needle from the pen. 

 

 

 

 

 

 

 

 

Ask your pharmacist how to throw away the needle you no longer use. 

Replace the pen cap. 

 

Step F. Repeat all steps in Section 3 for each injection. 

 

Throw away a pen 14 days after activation. Do this even if there is some medicine left in the pen. 

 

Once you have thrown away the green pen continue to Section 4 to begin using the purple pen. 

 

 

Section 4 – MOVING TO THE PURPLE PEN 

 

Completed use of the green 10 microgram pen 

 

 



 

80 

 
The green 10 micrograms Lyxumia pen is empty when the black plunger has reached ‘0’ on the dose 

scale and the injection button cannot be pulled out fully. 
 

Once the green 10 micrograms Lyxumia pen is empty you must continue your treatment by taking 

your next injection when it is due, using the purple 20 microgram Lyxumia pen. This is used in exactly 
the same way. Use of purple 20 micrograms pen 

 

 
 

Purple 20 micrograms pen activation 
 

The purple 20 micrograms Lyxumia pen must also be activated before use. Follow all steps in Section 

2. 
 

Purple 20 microgram pen Use 

To inject a dose with the purple 20 micrograms Lyxumia pen, follow all steps in Section 3. Repeat 
Section 3 for your daily injections until your pen is empty. 

 

Table of activation and disposal 

In the table, write the date when you activated your pen and the date to throw it away 14 days later.  

 

Pen Date of activation Date to throw away 

10 microgram ___ / ___ / ___ ___ / ___ / ___ 

20 microgram ___ / ___ / ___ ___ / ___ / ___ 

 

Storage 

 

General information 

• Keep your Lyxumia pens in a safe place out of the reach and sight of children. 

• Protect your Lyxumia pens from dust and dirt. 

• Replace the pen cap after each use in order to protect from light. 

• Do not use Lyxumia after the expiry date which is stated on the label and on the carton. The 
expiry date refers to the last day of that month. 

 

Before activation of the pen: 

• Store your unused Lyxumia pens in the refrigerator, 2°C to 8°C.  

• Do not freeze Lyxumia pens and do not use Lyxumia if it has been frozen. 

• Allow your pen to warm at room temperature before using.  
 

After activation of the pen: 

• Once activated, store your Lyxumia pen below 30°C. Do not freeze Lyxumia once it has been 
activated. 

• Do not store your Lyxumia pen with the needle attached. An attached needle might lead to 
contamination and possible intake of air which might impact the dose accuracy. 

• Once your Lyxumia pen is activated it can be used for up to 14 days. Throw away a used 
Lyxumia pen after 14 days. Do this even if there is some medicine left in the pen. 

 



 

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Disposal 

• Replace the pen cap before you throw away your Lyxumia pen.  

• Throw away your Lyxumia pen, ask your pharmacist how to throw away medicines you no longer 
use. 

 

Maintenance 

 

• Handle your Lyxumia pen with care. 

• You can clean the outside of your Lyxumia pen by wiping it with a damp cloth. 

• Do not soak, wash or put liquid on (lubricate) your Lyxumia pen, this may damage it. 

• If you think your Lyxumia pen may be damaged, do not use it. Get a new one. Do not try to repair 
the pen. 

 
 

 

Injection sites 

 

  
 

Lyxumia must be injected under the skin and can be injected in any of the areas shown above in blue. 

These are the thigh, abdomen or upper arm. Ask your doctor, pharmacist or nurse about how to inject 

correctly. 

 

 

Questions and answers 

 

What if I forget to activate the Lyxumia pen or inject myself before activation? 

If you have injected yourself before activating the pen, do not correct this by giving yourself a second 

injection. Contact your doctor, pharmacist or nurse for advice on checking your blood sugar. 

 

What if there are air bubbles in the container? 

Small air bubbles in the container are normal - they will not harm you. Your dose will be correct and 

you can keep following the instructions. Contact your doctor, pharmacist or nurse if you need help. 

 

What if no liquid comes out during activation? 

The needle may be blocked or not properly screwed on. Remove the needle from the pen, attach a new 

one and repeat Steps 4 and 5 only. If still no liquid comes out, your Lyxumia pen may be damaged. Do 

not use this Lyxumia Treatment Initiation pack. Contact your doctor, pharmacist or nurse for help. 

 

What if it is hard to press the injection button all the way in? 

The needle may be blocked or not properly screwed on. Pull the needle out of your skin and remove 

the needle from the pen. Attach a new needle and repeat Steps D and E only. If it is still hard to press 

the injection button, your Lyxumia pen may be damaged. Do not use this Lyxumia Treatment 

Initiation pack. Contact your doctor, pharmacist or nurse for help. 

 

 

Back Front 



 

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If you have any questions about Lyxumia or about diabetes, ask your doctor, pharmacist or nurse or 

call the local sanofi-aventis number in the Lyxumia “Package leaflet: Information for the user” 

(provided separately in the box).