Insulin glargine and Lixisenatide

Frequent glucose monitoring and dose adjustment may be necessary for insulin glargine/lixisenatide in patients with hepatic impairment.

In patients with mild to moderate renal impairment using insulin glargine/lixisenatide, frequent glucose monitoring and dose adjustment may be necessary.

Insulin glargine/lixisenatide combination is not recommended in patients with severe renal impairment and end-stage renal disease as there is no sufficient therapeutic experience with use of lixisenatide.

There is no clinical data on exposed pregnancies from controlled clinical studies with use of insulin glargine/lixisenatide combination, insulin glargine, or lixisenatide.

A large amount of data on pregnant women (more than 1,000 pregnancy outcomes) with insulin glargine indicate no malformative nor feto/neonatal toxicity of insulin glargine. Animal data do not indicate reproductive toxicity with insulin glargine.

There are no or limited amount of data from the use of lixisenatide in pregnant women. Studies with lixisenatide in animals have shown reproductive toxicity.

Insulin glargine/lixisenatide combination is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is unknown whether insulin glargine or lixisenatide are excreted in human milk. A risk to the newborns/infants cannot be excluded. Breast-feeding should be discontinued during treatment with insulin glargine/lixisenatide.

Women of childbearing potential

Insulin glargine/lixisenatide combination is not recommended in women of childbearing potential not using contraception.

Fertility

Animal studies with lixisenatide or insulin glargine do not indicate direct harmful effects with respect to fertility.

Insulin glargine/lixisenatide combination has no or negligible influence on the ability to drive or use machines. However, the patient’s ability to concentrate and react may be impaired as a result of hypoglycaemia or hyperglycaemia or, for example, as a result of visual impairment. This may constitute a risk in situations where these abilities are of special importance (e.g., driving a car or using machines).

Patients should be advised to take precautions to avoid hypoglycaemia while driving and using machines. This is particularly important in those who have reduced or absent awareness of the warning symptoms of hypoglycaemia or have frequent episodes of hypoglycaemia. It should be considered whether it is advisable to drive or use machines in these circumstances.

Summary of the safety profile

The most frequently reported adverse reactions during treatment with insulin glargine/lixisenatide were hypoglycaemia and gastrointestinal adverse reactions (see section ‘Description of selected adverse reactions’ below).

Tabulated list of adverse reactions

The following related adverse reactions from clinical investigations are listed below by system organ class and in order of decreasing frequency (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; not known: cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse drug reactions reported:

Description of selected adverse reactions

Hypoglycaemia

The following table describes the rate of documented symptomatic hypoglycaemia (≤3.9 mmol/L) and severe hypoglycaemia for both insulin glargine/lixisenatide and the comparator***.

Table 2. Documented symptomatic or severe hypoglycaemic adverse reactions:

^* Documented symptomatic hypoglycaemia was an event during which typical symptoms of hypoglycaemia were accompanied by a measured plasma glucose concentration of ≤3.9 mmol/L.
^** Severe symptomatic hypoglycaemia was an event requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.
^*** Liraglutide, exenatide BID (twice in a day) or extended release, dulaglutide or albiglutide

Gastrointestinal disorders

Gastrointestinal adverse reactions (nausea, vomiting and diarrhoea) were frequently reported adverse reactions during the treatment period. In patients treated with insulin glargine/lixisenatide, the incidence of related nausea, diarrhoea and vomiting was 8.4%, 2.2% and 2.2%, respectively. Gastrointestinal adverse reactions were mostly mild and transient in nature.

Immune system disorders

Allergic reactions (urticaria) possibly related with insulin glargine/lixisenatide have been reported in 0.3% of patients. Cases of generalised allergic reaction including anaphylactic reaction and angioedema have been reported during marketed use of insulin glargine and lixisenatide.

Immunogenicity

Administration of insulin glargine/lixisenatide may cause formation of antibodies against insulin glargine and/or lixisenatide.

The incidence of formation of anti-insulin glargine antibodies was 21% and 26.2%. In approximately 93% of the patients, anti-insulin glargine antibodies showed cross-reactivity to human insulin. The incidence of formation of anti-lixisenatide antibodies was approximately 43%. Neither status for antiinsulin glargine antibodies nor for anti-lixisenatide antibodies had a clinically relevant impact on safety or efficacy.

Skin and subcutaneous tissue disorders

Lipodystrophy and cutaneous amyloidosis may occur at the injection site of insulins and delay local insulin absorption. Continuous rotation of the injection site within the given injection area may help to reduce or prevent these reactions.

Injection site reactions

Some (1.7%) patients using insulin containing therapy, including insulin glargine/lixisenatide have experienced erythema, local oedema, and pruritus at the site of injection.

Heart rate

Increase in heart rate has been reported with GLP-1 receptor agonist use and a transient increase was also observed in some studies with lixisenatide. No increase in mean heart rate was seen in all phase 3 studies with insulin glargine/lixisenatide.