Adverse reactions : תופעות לוואי

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 diarrhea. These reactions were mostly mild and transient.

In addition, hypoglycemia (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.

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                                        Influenza infestations
Upper respiratory tract infection

Cystitis
Viral infection
Immune system                                                                 Anaphylactic reaction disorders
Metabolism and            Hypoglycemia (in         Hypoglycemia (in nutrition disorders       combination with a       combination with sulphonylurea and / or a metformin alone) basal insulin)
Nervous system            Headache                  Dizziness disorders
Somnolence
Gastrointestinal          Nausea                    Dyspepsia disorders                 Vomiting
Diarrhea
Skin and subcutaneous                                                         Urticaria tissue disorders
Musculoskeletal and                                 Back pain connective tissue disorders
General disorders and                               Injection site pruritus administration site conditions


Description of selected adverse reactions
Hypoglycemia
In patients taking Lyxumia in monotherapy, symptomatic hypoglycemia 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 hypoglycemia 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 hypoglycemia 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 hypoglycemia 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 hypoglycemia 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 hypoglycemia occurred in 47.2% of lixisenatide treated patients compared to 21.6% with placebo (25.6% absolute difference).

Overall, the incidence of severe symptomatic hypoglycemia 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 occured 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 glycemic 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.

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form at https://sideeffects.health.gov.il/.