Significant adverse events are also described in the PRECAUTIONS section. The adverse events with QTERN are consistent with the adverse events for each component. For further information on adverse effects associated with the saxagliptin and dapagliflozin refer to the appropriate individual Product Information document.
Clinical trials: Saxagliptin/dapagliflozin fixed-dose combination has been demonstrated to be bioequivalent with co-administered saxagliptin and dapagliflozin. In therapeutic clinical trials, saxagliptin and dapagliflozin were administered as individual tablets.
The safety of combined use of 5 mg saxagliptin and 10 mg dapagliflozin has been evaluated in 1169 adult subjects with type 2 diabetes (T2DM) in an integrated safety pool of three phase 3 active/placebo controlled short-term and long-term clinical trials for up to 52 weeks. The median exposure for the saxagliptin plus dapagliflozin plus metformin group was 359 days. At least 235 subjects in the saxagliptin plus dapagliflozin plus metformin group received saxagliptin/dapagliflozin for >360 days. The pooled safety analysis is comprised of 3 treatment groups: saxagliptin plus dapagliflozin plus metformin (492 subjects; data pooled from the concomitant therapy with saxagliptin and dapagliflozin study and the 2 sequential combination use studies); saxagliptin plus metformin (336 subjects data pooled from the concomitant therapy with saxagliptin and dapagliflozin and the dapagliflozin added to saxagliptin and metformin studies); and dapagliflozin plus metformin (341 subjects data pooled from the concomitant therapy with saxagliptin and dapagliflozin and the saxagliptin added to dapagliflozin and metformin studies). The safety profile of the combined use of saxagliptin plus dapagliflozin in these trials was comparable to the individual monocomponents (see Table 3). The incidence of hypoglycaemia was low (1.4%). No episodes of major hypoglycaemia were reported, and no subject discontinued the study treatment due to hypoglycaemia. (See Table 3.)
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Additional adverse reactions occurring at frequency of ≥2% and more than ≥1% more frequently compared to placebo in the mono-component clinical programs for saxagliptin and dapagliflozin included gastroenteritis, vomiting and polyuria.
Diabetic ketoacidosis was identified with a frequency of rare ( ≥1/10,000 to < 1/1000), based on annual rate, in a large cardiovascular outcomes study with dapagliflozin in patients with type 2 diabetes.
Description of selected adverse events: The information as follows provides additional information regarding adverse events reported for the saxagliptin/dapagliflozin combination.
Hypoglycaemia: Saxagliptin/dapagliflozin combination The overall incidence of hypoglycaemia for the pooled safety data patients was low (1.4%) in the saxagliptin plus dapagliflozin plus metformin group, 0.3% in the saxagliptin plus metformin group, and 1.8% in dapagliflozin plus metformin group. No episodes of major hypoglycaemia were reported, and no subject discontinued the study treatment due to hypoglycaemia.
Urinary Tract Infections: Saxagliptin/dapagliflozin combination: In the pooled safety analysis, urinary tract infections were balanced across the 3 treatment groups: 5.7% in the saxagliptin plus dapagliflozin plus metformin group, 7.4% in the saxagliptin plus metformin group and 5.6% in the dapagliflozin plus metformin group. The majority of the urinary tract infection adverse events were reported in females (81% of subjects with urinary tract infection), and were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.
Genital Infections: Saxagliptin/dapagliflozin combination: The reported adverse events of vulvovaginitis, balanitis and related genital infections from pooled safety analysis were reflective of the safety profile with dapagliflozin. Adverse events of genital infection were reported in 3.0% in the saxagliptin plus dapagliflozin plus metformin group, 0.9% of saxagliptin plus metformin group and 5.9% of subjects in the dapagliflozin plus metformin group. The majority of the genital infections were reported in females (84% of subjects with a genital infection), and were mild or moderate in intensity, of single occurrence and most patients continued on therapy.
Diabetic ketoacidosis (DKA): Dapagliflozin: In a large cardiovascular outcomes study with dapagliflozin in patients with type 2 diabetes, where 8574 patients received dapagliflozin 10 mg and 8569 patients received placebo, with a median exposure time of 48 months, events of DKA were reported in 27 patients in the dapagliflozin 10 mg group and 12 patients in the placebo group. The events occurred evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin group, 22 had concomitant insulin treatment at the time of the event. Precipitating factors for DKA were as expected in a type 2 diabetes mellitus population (see PRECAUTIONS).
Volume depletion: Saxagliptin/dapagliflozin combination: Events related to volume depletion (hypotension, dehydration, and hypovolemia) were reflective of the adverse events with dapagliflozin and were reported in two subjects (0.4%) in the saxagliptin plus dapagliflozin plus metformin group (SAE of syncope and an adverse event of urine output decreased), and 3 subjects (0.9%) in the dapagliflozin plus metformin group (2 adverse events of syncope and 1 of hypotension).
Events Related to Decreased Renal Function: Saxagliptin/dapagliflozin combination: In the pooled safety analysis, the incidence of adverse events related to decreased renal function was 2.0% of subjects in the saxagliptin plus dapagliflozin plus metformin group, 1.8% of subjects in the saxagliptin plus metformin group, and 0.6% of subjects in the dapagliflozin plus metformin group. Subjects with adverse events of renal impairment had lower mean eGFR values at baseline of 61.8 mL/min/1.73 m2 compared to 93.6 mL/min/1.73 m2 in overall population. The majority of events were considered non-serious, mild or moderate in intensity, and resolved.
Dapagliflozin: In the 13 study, short-term, placebo controlled dapagliflozin study pool, adverse events related to increased creatinine were grouped (e.g. decreased renal creatinine clearance, renal impairment, increased blood creatinine and decreased glomerular filtration rate). This grouping of events was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively.
In patients with normal renal function or mild renal impairment (baseline eGFR ≥60 mL/min/1.73 m2) this grouping of events were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively. These events were more common in patients with baseline eGFR ≥30 and <60 mL/min/1.73 m2 (18.5% dapagliflozin 10 mg vs 9.3% placebo).
Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of ≤44 μmol/L from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.
Cardiovascular Safety: Saxagliptin/dapagliflozin combination: CV events that were adjudicated and confirmed as CV events were reported in a total of 1.0% of subjects in the saxagliptin plus dapagliflozin plus metformin group, 0.6% in the saxagliptin plus metformin group, and 0.9% in the dapagliflozin plus metformin group.
Saxagliptin: In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR) Trial, the effect of ONGLYZA (saxagliptin) on the occurrence of major cardiovascular disease (CVD) events was assessed in 16,492 adult patients with type 2 diabetes who had either established CVD or multiple risk factors for vascular disease. Patients were randomly assigned to placebo (n=8212) or saxagliptin (5 mg or 2.5 mg for patients with moderate or severe renal insufficiency) once daily (n=8280). The demographics and baseline characteristics of subjects were balanced between the saxagliptin and placebo groups. Subjects were followed for a mean duration of 2 (median=2.0) years.
The primary safety and efficacy endpoint was a composite endpoint consisting of the time-to-first occurrence of any of the following major adverse CV events (MACE): CV death, non-fatal myocardial infarction, or non-fatal ischaemic stroke.
Saxagliptin did not increase the CV risk (CV death, nonfatal myocardial infarction, or nonfatal ischemic stroke) in patients with T2DM compared to placebo when added to current background therapy (HR 1.00; 95% CI: 0.89, 1.12; P<0.001 for non-inferiority).
One component of the secondary composite endpoint, 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].
Dapagliflozin: A meta-analysis of adjudicated cardiovascular events in the clinical program (21 Phase 2b and 3 studies) was performed. In the clinical program, 34.4% of subjects had a history of cardiovascular disease (excluding hypertension) at baseline and 67.9% had hypertension. The hazard ratio comparing dapagliflozin to comparator was 0.79 (95 % CI: 0.58, 1.07), indicating that in this analysis dapagliflozin is not associated with an increase in cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovascular death, MI and stroke were observed with a hazard ratio of 0.77 (95 % CI: 0.54, 1.10).
Malignancies: Saxagliptin/dapagliflozin combination: Malignant and unspecified neoplasms were reported in 3 subjects included in the short-term combination pooled safety data. They included adverse events of gastric neoplasm, pancreatic cancer with hepatic metastases, and invasive ductal breast carcinoma in the saxagliptin plus dapagliflozin plus metformin group. Considering the short latency between first drug exposure and tumour diagnosis, a causal relationship to any specific tumour type is considered unlikely.
Dapagliflozin: During clinical trials, the overall proportion of subjects with malignant or unspecified tumours was similar between those treated with dapagliflozin (1.50%) and placebo/comparator (1.50%), and there was no carcinogenicity or mutagenicity signal in animal data (see Precautions). When considering the cases of tumours occurring in the different organ systems, the relative risk associated with dapagiflozin was above 1 for some tumours (bladder, prostate, breast) and below 1 for others (e.g. blood and lymphatic, ovary, renal tract), not resulting in an overall increased tumour risk associated with dapagliflozin. The increased/decreased risk was not statistically significant in any of the organ systems. Considering the lack of tumour findings in non-clinical studies as well as the short latency between first drug exposure and tumour diagnosis, a causal relationship is considered unlikely. Since the numerical imbalance of breast, bladder and prostate tumours must be considered with caution, it will be further investigated in post-authorisation studies.
Vital signs: Saxagliptin/dapagliflozin combination: Mean change from baseline in the heart rates across the 3 treatment groups were similar. Consistent with its mild diuretic effects, the dapagliflozin-containing treatments were associated with decreases in systolic and diastolic blood pressure. The small effects on blood pressure were consistent over time. A similar proportion of subjects in each of the three treatment groups achieved systolic blood pressure <130 mmHg and diastolic blood pressure <80 mmHg.
Peripheral Oedema: Saxagliptin: In a saxagliptin add-on to TZD study, the incidence of peripheral oedema was higher for saxagliptin 5 mg plus TZD versus placebo plus TZD (8.1% versus 4.3%). However, in saxagliptin monotherapy the overall incidence of peripheral oedema was similar to placebo. In the SAVOR study, the overall incidence of adverse reactions of peripheral oedema observed in patients treated with saxagliptin was similar to those treated with placebo (3.9% versus 4% respectively).
Hypersensitivity reactions: Saxagliptin: A grouping of hypersensitivity-related events in the saxagliptin 5-study pooled analysis up to Week 24 showed an incidence of 1.5% and 0.4% in patients who received saxagliptin 5 mg and placebo, respectively. None of these events in patients who received saxagliptin required hospitalisation or were reported to be life-threatening by the investigators.
Laboratory Findings: Saxagliptin/dapagliflozin combination: The frequency of marked abnormalities in laboratory tests results in the pooled safety analysis was low and similar across the treatment groups (see Precautions-Effect on laboratory tests).
Post-marketing experience: The following post-marketing case reports have been reported during post-approval use of the monocomponents. Because these cases are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency.
Dapagliflozin: Metabolism and nutrition disorders - Ketoacidosis.
Infections and infestations - Serious urinary tract infections such as pyelonephritis, urosepsis, necrotising fasciitis of the perineum (Fournier's gangrene).
Skin and subcutaneous tissue disorders - Rash.
Saxagliptin: Gastrointestinal disorders - Acute pancreatitis.
Musculoskeletal and connective tissue disorders - Arthralgia.
Immune system disorders - Hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria.
Skin and subcutaneous tissue disorders - bullous pemphigoid.