Adverse reactions : תופעות לוואי

4.8      Undesirable effects

Summary of the safety profile
The most frequently reported adverse reactions during treatment with Suliqua 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

System organ class                                 Frequency
Very common     Common             Uncommon             Rare           Not Known Infections and                                                 Nasopharyngitis infestations                                                   Upper respiratory tract infection
Immune system                                                  Urticaria di  d
Metabolism                  Hypoglycaemia and nutrition di   d system
Nervous                                     Dizziness          Headache disorders                                                      Dysgeusia Gastrointestinal                            Nausea             Dyspepsia            Delayed disorders                                   Diarrhoea          Abdominal pain       gastric Vomiting                                emptying
Hepatobiliary                                                  Cholelithiasis disorders                                                      Cholecystitis 
Skin and                                                                                           Cutaneous subcutaneous                                                                                       amyloidosis tissue disorders                                                                                   Lipodystrophy General disorders                           Injection site     Fatigue and administration                          reactions




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 Suliqua and the comparator***.

Table 2: Documented symptomatic or severe hypoglycaemic adverse reactions 
Insulin naïve patients            Switch from         Switch from GLP-1 basal insulin       receptor agonist***
GLP-1
Insulin                               Insulin           receptor
Suliqua   glargine Lixisenatide      Suliqua    glargine  Suliqua agonist***
N                 469       467            233         365          365     255         256 Documented symptomatic hypoglycaemia*
Patients with event,   120               110         15            146       155          71          6 n (%)                (25.6%)           (23.6%)     (6.4%)        (40.0%)   (42.5%)     (27.8%)     (2.3%) Events per patient- year, n                1.44             1.22        0.34            3.03     4.22       1.54        0.08 Severe hypoglycaemia**

Events per patient-
<0.01         0 year, n                         0      <0.01            0           0.02    <0.01 * 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 Suliqua, 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 Suliqua 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 Suliqua 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 anti-insulin 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 (see section 4.4).

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

Heart rate
Increase in heart rate has been reported with GLP-1receptor 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 Suliqua.

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/.