Adverse reactions : תופעות לוואי

4.8      Undesirable effects

Summary of the safety profile
The Xultophy clinical development programme included approximately 1,900 patients treated with Xultophy.

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

Tabulated list of adverse reactions

Adverse reactions associated with Xultophy are given below, listed by system organ class and frequency. Frequency categories 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) and not known (cannot be estimated from the available data).

Table 1 Adverse reactions reported in phase 3 controlled studies
MedDRA System organ class Frequency                  Adverse reaction Immune system disorders         Uncommon             Urticaria
Uncommon             Hypersensitivity
Unknown              Anaphylactic reaction
Metabolism and nutrition        Very common          Hypoglycaemia disorders                       Common               Decreased appetite Uncommon             Dehydration
Nervous system disorders        Common               Dizziness
Uncommon             Dysgeusia
Gastrointestinal disorders              Common           Nausea, diarrhoea, vomiting, constipation, dyspepsia, gastritis, abdominal pain,
gastroesophageal reflux disease, abdominal distension
Uncommon         Eructation, flatulence
Unknown          Pancreatitis (including necrotising pancreatitis )
Delayed gastric emptying
Hepatobiliary disorders                 Uncommon         Cholelithiasis Uncommon         Cholecystitis
Skin and subcutaneous tissue            Uncommon         Rash disorders                               Uncommon         Pruritus
Uncommon         Lipodystrophy acquired
Not known        Cutaneous amyloidosis†
General disorders and                   Common           Injection site reaction administration site condition           Unknown          Peripheral oedema Investigation                           Common           Increased lipase Common           Increased amylase
Uncommon         Increased heart rate
† ADR from postmarketing sources.


Description of selected adverse reactions
Hypoglycaemia
Hypoglycaemia may occur if the Xultophy dose is higher than required. Severe hypoglycaemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or even death. The symptoms of hypoglycaemia usually occur suddenly. They may include cold sweats, cool pale skin, fatigue, nervousness or tremor, anxiousness, unusual tiredness or weakness, confusion, difficulty in concentration, drowsiness, excessive hunger, vision changes, headache, nausea and palpitation. For frequencies of hypoglycaemia, please see section 5.1.

Allergic reactions
Allergic reactions (manifested with signs and symptoms such as urticaria (0.3% of patients treated with Xultophy), rash (0.7%), pruritus (0.5%) and/or swelling of the face (0.2%)) have been reported for Xultophy. Few cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnoea, and oedema have been reported during marketed use of liraglutide.
Anaphylactic reactions may potentially be life threatening.

Gastrointestinal adverse reactions
Gastrointestinal adverse reactions may occur more frequently at the beginning of Xultophy therapy and usually diminish within a few days or weeks on continued treatment. Nausea was reported in 7.8% of patients and was transient in nature for most patients. The proportion of patients reporting nausea per week at any point during treatment was below 4%. Diarrhoea and vomiting were reported in 7.5% and 3.9% of patients, respectively. The frequency of nausea and diarrhoea was ‘Common’ for Xultophy and ‘Very common’ for liraglutide. In addition, constipation, dyspepsia, gastritis, abdominal pain, gastroesophageal reflux disease, abdominal distension, eructation, flatulence and decreased appetite have been reported in up to 3.6% of patients treated with Xultophy.

Injection site reactions
Injection site reactions (including injection site haematoma, pain, haemmorrhage, erythema, nodules, swelling, discolouration, pruritus, warmth and injection site mass) have been reported in 2.6% of patients treated with Xultophy. These reactions were usually mild and transitory and they normally disappear during continued treatment.

Skin and subcutaneous tissue disorders
Lipodystrophy (including lipohypertrophy, lipoatrophy) and cutaneous amyloidosis may occur at the injection site 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).

Increased heart rate
Mean increase in heart rate from baseline of 2 to 3 beats per minute has been observed in clinical trials with Xultophy. In the LEADER trial, no long-term clinical impact of increased heart rate on the risk of cardiovascular events was observed with liraglutide (a component of Xultophy) (see section 5.1).


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 https://sideeffects.health.gov.il