Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 4.4 - Special warnings and precautions for use
• Change to section 5.1 - Pharmacodynamic properties
• Change to section 5.2 - Pharmacokinetic properties

Date of revision of text on the SPC: 02-May-2016

Legal Category:POM

Black Triangle (CHM): YES

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Update of sections 4.2, 4.4, 5.1 and 5.2 of the SmPC in order to update the safety information on Older Patients with Type 2 Diabetes Mellitus Inadequately Controlled on their Current Diabetes Treatment Regimen and on Patients with renal impairment following submission of study EFC12703 in fulfilment of MEA 006.

Reasons for adding or updating:

• Change to section 4.4 - Special warnings and precautions for use
• Change to section 5.1 - Pharmacodynamic properties
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 01-Apr-2016

Legal Category:POM

Black Triangle (CHM): YES

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Section 4.4 and 5.1-

Section 5.1-

• 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.

 

A meta-analysis of all independently adjudicated cardiovascular events (CV death, non-fatal myocardial infarction, non-fatal stroke, hospitalization for unstable angina, hospitalization for heart failure and coronary revascularization procedure) from 8 phase III placebo-controlled studies which included 2673 type 2 diabetes patients treated with lixisenatide and 1448 patients treated with placebo showed a hazard ratio of 1.03 (95% confidence interval 0.64, 1.66) for lixisenatide versus placebo. The number of events in the clinical studies was low (1.9% in lixisenatide treated patients and 1.8% in placebo treated patients), precluding firm conclusions. The incidence of the individual CV events (lixisenatide vs placebo) was: CV death (0.3% vs 0.3%), non-fatal myocardial infarction (0.4% vs 0.4%), non-fatal stroke (0.7% vs 0.4%), hospitalization for unstable angina (zero vs 0.1%), hospitalization for heart failure (0.1% vs zero), and coronary revascularization procedure (0.7% vs 1.0%).

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

 

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

 

 

 

Section 4.4-

Populations not studied

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

There is limited experience in patients with congestive heart failure.

Reasons for adding or updating:

• Change to section 2 - Qualitative and quantitative composition
• Change to section 5.1 - Pharmacodynamic properties

Date of revision of text on the SPC: 23-Oct-2014

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Section 2: minor typo corrected on the content of metacresol
Section 5.1: Pharmacodynamic effects updated as follows:

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 AUC  _0:30-4:30 h of plasma glucose after a test‑meal was: ‑12.,61 h*mmol/L (‑227.25 h*mg/dlL (-12,61 h*mmol/L) in the lixisenatide group and ‑4.04 h*mmol/L (‑-72.83 h*mg/dlL (-4.04 h*mmol/L) 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.

Reasons for adding or updating:

• Change to section 4.2 - Posology and method of administration
• Change to section 4.4 - Special warnings and precautions for use
• Change to section 5.1 - Pharmacodynamic properties
• Change to section 10 - Date of revision of the text

Date of revision of text on the SPC: 26-Jun-2014

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Black Triangle (CHM): YES

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Sections 4.2 & 5.1 updated to change timing of administration based on the main meal study results.
Section 4.4 updated to include reported events of acute pancreatitis with lixisenatide.

Reasons for adding or updating:

• Change to section 4.8 - Undesirable effects
• Change to section 5.1 - Pharmacodynamic properties
• Change to section 9 - Date of first authorisation/renewal of the authorisation
• Addition of black triangle

Date of revision of text on the SPC: 04-Oct-2013

Legal Category:POM

Black Triangle (CHM): YES

Free-text change information supplied by the pharmaceutical company:

Addition of Black Triangle
Section 4.8 updated to include the new PV Legislation wording on adverse effect reporting.
Section 5.1 updated to include the new ATC code.

Reasons for adding or updating:

• New SPC for new product

Legal Category:POM

Black Triangle (CHM): YES