Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
In five large long-term clinical phase 3a trials over 2,500 adult patients have received treatment with Victoza alone or in combination with metformin, a sulfonylurea (with or without metformin) or metformin plus rosiglitazone.

The most frequently reported adverse reactions during clinical trials were gastrointestinal disorders: nausea and diarrhoea were very common, whereas vomiting, constipation, abdominal pain, and dyspepsia were common. At the beginning of the therapy, these gastrointestinal adverse reactions may occur more frequently. These reactions usually diminish within a few days or weeks on continued treatment. Headache and nasopharyngitis were also common. Furthermore, hypoglycaemia was common, and very common when liraglutide is used in combination with a sulfonylurea. Severe hypoglycaemia has primarily been observed when combined with a sulfonylurea.

Tabulated list of adverse reactions

Table 1 lists adverse reactions reported in long-term phase 3a controlled trials, the LEADER trial (a long-term cardiovascular outcome trial) and spontaneous (post-marketing) reports. Frequencies for all events have been calculated based on their incidence in phase 3a clinical trials.
Frequencies 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); 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 reactions from long-term controlled phase 3a trials, the long-term cardiovascular outcome trial (LEADER) and spontaneous (post-marketing) reports 
MedDRA system organ       Very common            Common             Uncommon            Rare         Very rare classes
Infections and                       Nasopharyngitis infestations                         Bronchitis
Immune system                                                                Anaphylactic disorders                                                                    reactions Metabolism and                       Hypoglycaemia          Dehydration nutrition                            Anorexia disorders                            Appetite decreased
Nervous system                       Headache               Dysgeusia disorders                            Dizziness
Cardiac                              Increased heart rate disorders
Gastrointestinal   Nausea            Vomiting               Delayed          Intestinal     Pancreatitis disorders          Diarrhoea         Dyspepsia              gastric          obstruction    (including Abdominal pain         emptying                        necrotising upper                                                  pancreatitis)
Constipation
Gastritis
Flatulence
Abdominal distension
Gastroesophageal reflux disease
Abdominal discomfort
Toothache
Hepatobiliary                                               Cholelithiasis disorders                                                   Cholecystitis Skin and                             Rash                   Urticaria subcutaneous                                                Pruritus tissue disorder

Renal and                                                  Renal urinary                                                    impairment disorders                                                  Renal failure acute
General                              Fatigue               Malaise disorders and                        Injection site administration                       reactions site conditions
Investigations                       Increased lipase*
Increased amylase*
* From controlled phase 3b and 4 clinical trials only where they were measured.

Description of selected adverse reactions
In a clinical trial with liraglutide as monotherapy, rates of hypoglycaemia reported with liraglutide were lower than rates reported for patients treated with active comparator (glimepiride). The most frequently reported adverse reactions were gastrointestinal disorders, infections and infestations.

Hypoglycaemia
Most episodes of confirmed hypoglycaemia in clinical trials were minor. No episodes of severe hypoglycaemia were observed in the trial with liraglutide used as monotherapy. Severe hypoglycaemia may occur uncommonly and has primarily been observed when liraglutide is combined with a sulfonylurea (0.02 events/patient year). Very few episodes (0.001 events/patient year) were observed with administration of liraglutide in combination with oral antidiabetics other than sulfonylureas. The risk of hypoglycaemia is low with combined use of basal insulin and liraglutide (1.0 events per patient year, see section 5.1). In the LEADER trial, severe hypoglycaemic episodes were reported at a lower rate with liraglutide vs placebo (1.0 vs 1.5 events per 100 patient years; estimated rate ratio 0.69 [0.51 to 0.93]) (see section 5.1). For patients treated with premix insulin at baseline and at least for the following 26 weeks, the rate of severe hypoglycaemia for both liraglutide and placebo was 2.2 events per 100 patient years.

Gastrointestinal adverse reactions
When combining liraglutide with metformin, 20.7% of patients reported at least one episode of nausea, and 12.6% of patients reported at least one episode of diarrhoea. When combining liraglutide with a sulfonylurea, 9.1% of patients reported at least one episode of nausea and 7.9% of patients reported at least one episode of diarrhoea. Most episodes were mild to moderate and occurred in a dose-dependent fashion. With continued therapy, the frequency and severity decreased in most patients who initially experienced nausea.

Patients >70 years may experience more gastrointestinal effects when treated with liraglutide.
Patients with mild and moderate renal impairment (creatinine clearance 60–90 ml/min and 30– 59 ml/min, respectively) may experience more gastrointestinal effects when treated with liraglutide.

Cholelithiasis and cholecystitis
Few cases of cholelithiasis (0.4%) and cholecystitis (0.1%) have been reported during long-term, controlled phase 3a clinical trials with liraglutide. In the LEADER trial, the frequency of cholelithiasis and cholecystitis was 1.5% and 1.1% for liraglutide and 1.1% and 0.7% for placebo, respectively (see section 5.1).

Withdrawal
The incidence of withdrawal due to adverse reactions was 7.8% for liraglutide-treated patients and 3.4% for comparator-treated patients in the long-term controlled trials (26 weeks or longer). The most frequent adverse reactions leading to withdrawal for liraglutide-treated patients were nausea (2.8% of patients) and vomiting (1.5%).

Injection site reactions
Injection site reactions have been reported in approximately 2% of patients receiving Victoza in long- 
term (26 weeks or longer) controlled trials. These reactions have usually been mild.

Pancreatitis
Few cases of acute pancreatitis (<0.2%) have been reported during long-term, controlled phase 3 clinical trials with Victoza. Pancreatitis was also reported from marketed use. In the LEADER trial, the frequency of acute pancreatitis confirmed by adjudication was 0.4% for liraglutide and 0.5% for placebo, respectively (see sections 4.4 and 5.1).

Allergic reactions
Allergic reactions including urticaria, rash and pruritus have been reported from marketed use of Victoza.
Few cases of anaphylactic reactions with additional symptoms such as hypotension, palpitations, dyspnoea and oedema have been reported with marketed use of Victoza. Few cases (0.05%) of angioedema have been reported during all long-term clinical trials with Victoza.


Paediatric population
Overall, frequency, type and severity of adverse reactions in adolescents and children aged 10 years and above were comparable to that observed in the adult population. Rate of confirmed hypoglycaemic episodes was higher with liraglutide (0.58 events/patient year) compared to placebo (0.29 events/patient year). In patients treated with insulin prior to a confirmed hypoglycaemic episode the rate was higher with liraglutide (1.82 events/patient year) compared to placebo (0.91 events/patient years). No severe hypoglycaemic episodes occurred in the liraglutide treatment group.


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