Adverse reactions : תופעות לוואי

4.8 Undesirable effects

Summary of the safety profile
The most commonly reported adverse reactions in placebo-controlled trials reported in ≥ 5% of patients treated with Onglyza 5 mg and more commonly than in patients treated with placebo are upper respiratory tract infection (7.7%), urinary tract infection (6.8%) and headache (6.5%).


There were 4,148 patients with type 2 diabetes, including 3,021 patients treated with Onglyza, randomised in six double-blind, controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control.

In randomised, controlled, double-blind clinical trials (including developmental and postmarketing experience), over 17,000 patients with type 2 diabetes have been treated with Onglyza.
. In a pooled analysis of 1,681 patients with type 2 diabetes including 882 patients treated with Onglyza 5 mg, randomised in five double-blind, placebo-controlled clinical safety and efficacy studies conducted to evaluate the effects of saxagliptin on glycaemic control, the overall incidence of adverse events in patients treated with saxagliptin 5 mg was similar to placebo.
Discontinuation of therapy due to adverse events was higher in patients who received saxagliptin 5 mg as compared to placebo (3.3% as compared to 1.8%).

Tabulated list of adverse reactions

Adverse reactions reported (in ≥5% of patients treated with saxagliptin 5 mg and more commonly than in patients treated with placebo or that were reported in ≥2% of patients treated with saxagliptin 5 mg and ≥1% more frequently compared to placebo from the pooled analysis of five studies of glycaemic control, plus an additional active-controlled study of initial combination with metformin are shown in Table 1.

The adverse reactions are listed by system organ class and absolute frequency. 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), or Very rare (<1/10,000), not known (cannot be estimated from the available data).

Table 1 Frequency of adverse reactions by system organ class from clinical trials and postmarketing experience


System organ            Frequency of adverse reactions by treatment regimen class Adverse
Reaction
Saxagliptin        Saxagliptin      Saxagliptin with     Saxagliptin with monotherapy        with             a sulphonylurea      a metformin1       (glibenclamide)      thiazolidinedione
Infections and infestations
Upper respiratory          Common            Common             Common                Common infection
Urinary tract           Common      Common        Common       Common infection
Gastroenteritis         Common     Common         Common       Common Sinusitis               Common     Common         Common       Common Nasopharyngitis                    Common2
Immune system disorders
Hypersensitivity       Uncommon    Uncommon      Uncommon     Uncommon reactions†‡
Anaphylactic             Rare        Rare           Rare        Rare reactions including anaphylactic shock†‡
Metabolism and nutrition disorders
Hypoglycaemia                                  Very common3
Dyslipidemia                                   Uncommon
Hypertri-                                      Uncommon
Glyceridemia
Nervous system disorders
Dizziness               Common
Headache                Common      Common        Common       Common Gastrointestinal disorders
Abdominal pain†         Common      Common        Common       Common Diarrhoea4              Common      Common        Common       Common Dyspepsia                           Common
Gastritis                           Common
Nausea†                 Common      Common        Common       Common Vomiting                Common      Common        Common       Common Pancreatitis†          Uncommon    Uncommon      Uncommon     Uncommon 
Constipation†          Not Known   Not Known     Not Known    Not Known 
Skin and subcutaneous tissue disorders
Rash†                   Common      Common        Common
Dermatitis†            Uncommon    Uncommon      Uncommon     Uncommon Pruritus†              Uncommon    Uncommon      Uncommon     Uncommon Urticaria†             Uncommon    Uncommon      Uncommon     Uncommon Angioedema†‡             Rare        Rare          Rare         Rare Bullous                Not known   Not known     Not known    Not known pemhigoid†
Musculo-skeletal and connective tissue disorders
Arthralgia                         Uncommon
Myalgia5                            Common
Reproductive system and breast disorders
Erectile dysfunction               Uncommon
General disorders and administration site conditions
Fatigue                    Common                            Uncommon Oedema peripheral                                                                     Common 
1
Includes saxagliptin in add-on to metformin and initial combination with metformin.
2
Only in the initial combination therapy.
3
There was no statistically significant difference compared to placebo. The incidence of confirmed hypoglycaemia was uncommon for Onglyza 5 mg (0.8%) and placebo (0.7%).
4 The incidence of diarrhoea was 4.1% (36/882) in the saxagliptin 5 mg group and 6.1% (49/799) in the
 placebo group.
5Asinitial combination with metformin, myalgia is reported as uncommon †Adverse   reactions were identified through postmarketing surveillance ‡See sections 4.3 and 4.4



SAVOR trial results
The SAVOR trial included 8240 patients treated with Onglyza 5 mg or 2.5 mg once daily and 8173 patients on placebo. The overall incidence of adverse events in patients treated with Onglyza in this trial was similar to placebo (72.5% versus 72.2%, respectively).
The incidence of adjudicated pancreatitis events was 0.3% in both Onglyza-treated patients and placebo- treated patients in the intent-to-treat population.
The incidence of hypersensitivity reactions was 1.1% in both Onglyza-treated patients and placebo-treated patients.
The overall incidence of reported hypoglycaemia (recorded in daily patient diaries) was 17.1% in subjects treated with Onglyza and 14.8% among patients treated with placebo. The percent of subjects with reported on-treatment events of major hypoglycemia (defined as an event that required assistance of another person) was higher in the saxagliptin group than in the placebo group (2.1% and 1.6%, respectively) The increased risk of overall hypoglycemia and major hypoglycemia observed in the saxagliptin-treated group occurred primarily in subjects treated with SU at baseline and not in subjects on insulin or metformin monotherapy at baseline. The increased risk of overall and major hypoglycemia was primarily observed in subjects with A1C < 7% at baseline.
Decreased lymphocyte counts were reported in 0.5% of Onglyza treated patients and 0.4% of placebo-treated patients.
Hospitalisation for heart failure, occurred at a greater rate in the saxagliptin group (3.5%) compared with the placebo group (2.8%), with nominal statistical significance favouring placebo [HR = 1.27; 95% CI 1.07, 1.51); P = 0.007]. See also section 5.1.

Description of selected adverse reactions
Hypoglycaemia
Adverse reactions of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucose measurement was not required.
When used as add-on combination therapy with metformin plus sulphonylurea, the overall incidence of reported hypoglycemia was 10.1 % for Onglyza 5 mg and 6.3% for placebo.
When used as add-on to insulin (with or without metformin), the overall incidence of reported hypoglycaemia was 18.4% for Onglyza 5 mg and 19.9% for placebo.


Investigations
Across clinical studies, the incidence of laboratory adverse events was similar in patients treated with saxagliptin 5 mg compared to patients treated with placebo. A small decrease in absolute lymphocyte count was observed. From a baseline mean absolute lymphocyte count of approximately 2,200 cells/μl, a mean decrease of approximately 100 cells/μl relative to placebo was observed in the placebo-controlled-pooled analysis. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration.
The decreases in lymphocyte count were not associated with clinically relevant adverse reactions. The clinical significance of this decrease in lymphocyte count relative to placebo is not known.
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