Lixisenatide

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.

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 C_max was reduced by 19% and t_max 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.

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 C_max, AUC, t_½ and t_max of ethinylestradiol and levonorgestrel were unchanged. Administration of the oral contraceptive 1 hour or 4 hours after lixisenatide did not affect AUC and t_½ of ethinylestradiol and levonorgestrel, whereas C_max of ethinylestradiol was decreased by 52% and 39% respectively and C_max of levonorgestrel was decreased by 46% and 20%, respectively and median t_max was delayed by 1 to 3 hours.

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

When lixisenatide 20 mcg and atorvastatin 40 mg were co-administered in the morning for 6 days, the exposure to atorvastatin was not affected, while C_max was decreased by 31% and t_max was delayed by 3.25 hours.

No such increase for t_max was observed when atorvastatin was administered in the evening and lixisenatide in the morning but the AUC and C_max of atorvastatin were increased by 27% and 66%, respectively.

These changes are not clinically relevant and therefore, no dose adjustment for atorvastatin is required when co-administered with lixisenatide.

After concomitant administration of lixisenatide 20 mcg and digoxin 0.25 mg at steady state, the AUC of digoxin was not affected. The t_max of digoxin was delayed by 1.5 hour and the C_max was reduced by 26%.

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

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 t_½ were unchanged whatever the timing of its administration (before or after the lixisenatide injection). When administered 1 or 4 hours after 10 mcg lixisenatide, C_max of paracetamol was decreased by 29% and 31% respectively and median t_max was delayed by 2.0 and 1.75 hours respectively. A further delay in t_max and a reduced C_max of paracetamol have been predicted with the 20 mcg maintenance dose.

No effects on paracetamol C_max and t_max were observed when paracetamol was administered 1 hour before lixisenatide.

Based on these results, no dose adjustment for paracetamol is required but the delayed t_max 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.

After concomitant administration of lixisenatide 20 mcg and ramipril 5 mg during 6 days, the AUC of ramipril was increased by 21% while the C_max was decreased by 63%. The AUC and C_max of the active metabolite (ramiprilat) were not affected. The t_max 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.

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.

Use of glucagon-like peptide-1 (GLP-1) receptor agonists has been associated with a risk of developing acute pancreatitis. Caution should be exercised in patients with a history of pancreatitis.

There are no adequate data from the use of lixisenatide in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Lixisenatide 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 lixisenatide should be discontinued.

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

Women of childbearing potential

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

Fertility

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

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

Summary of the safety profile

Over 2,600 patients have received lixisenatide 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 lixisenatide was used in combination with a sulphonylurea and/or a basal insulin) and headache occurred. Allergic reactions have been reported in 0.4% of lixisenatide 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 the table below. The table presents adverse reactions that occurred with an incidence >5% if the frequency was higher among lixisenatide treated patients than patients treated with all comparators. The table also includes adverse reactions with a frequency ≥1% in the lixisenatide 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.

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):

Description of selected adverse reactions

Hypoglycaemia

In patients taking lixisenatide in monotherapy, symptomatic hypoglycaemia occurred in 1.7% of lixisenatide treated patients and in 1.6% of placebo treated patients. When lixisenatide 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 lixisenatide 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 lixisenatide 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 lixisenatide 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 lixisenatide was given with a sulphonylurea and a basal insulin, symptomatic hypoglycaemia occurred in 47.2% of lixisenatide treated patients compared to 21.6% with placebo (25.6% absolute difference).

Overall, the incidence of severe symptomatic hypoglycaemia was uncommon (0.4% in lixisenatide patients and 0.2% in placebo patients) during the entire treatment period of the Phase III placebo-controlled studies.

Gastrointestinal disorders

Nausea and vomiting were the most frequently reported adverse reactions during the main 24-week treatment period. The incidence of nausea was higher in the lixisenatide group (26.1%) compared to the placebo group (6.2%) and the incidence of vomiting was higher in the lixisenatide group (10.5%) than in the placebo group (1.8%). They were mostly mild and transient and 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 lixisenatide 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 lixisenatide 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 HbA_1c from baseline was similar regardless of the antibody status (positive or negative). Of lixisenatide-treated patients with HbA_1c 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 HbA_1c 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 HbA_1c.

The antibody status (positive or negative) is not predictive of the reduction of HbA_1c for an individual patient.

There was no difference in the overall safety profile in patients regardless of the antibody status with the exception of an increase of the incidence of injection site reactions (4.7% in antibody positive patients compared to 2.5% in antibody-negative patients during the entire treatment period). The majority of injection site reactions were mild, regardless of antibody status.

There was no cross-reactivity versus either native glucagon or endogenous GLP-1.

Allergic reactions

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

Heart rate

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

Withdrawal

The incidence of treatment discontinuation due to adverse events was 7.4% for lixisenatide 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%).