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 and dapagliflozin plus metformin group was 359 days. At least 235 subjects in the saxagliptin and dapagliflozin plus metformin group received saxagliptin/dapagliflozin for >360 days. The pooled safety analysis is comprised of 3 treatment groups: saxagliptin and 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 6). 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 6.)
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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: The overall incidence of hypoglycaemia for the pooled safety data patients was low (2.0%) in the saxagliptin 5 mg plus dapagliflozin 10 mg plus metformin group, 0.6% in the saxagliptin plus metformin group, and 1.8% in dapagliflozin plus metformin group.
Saxagliptin and dapagliflozin plus metformin had lower incidence rates of hypoglycaemia compared to insulin or sulfonylurea. The overall incidence rates of hypoglycaemia for a 24-week study were 12.7% for the combination therapy plus metformin versus 33.1% for insulin plus metformin without sulfonylurea. The overall incidence rates for hypoglycaemia for two 52-week studies comparing the combination therapy plus metformin to glimepiride were: for the 1st study ,4.2% for the combination therapy plus metformin versus 27.9% for glimepiride plus metformin and 2.9% for dapagliflozin plus metformin; for the 2nd study 18.5% for the combination therapy plus metformin versus 43.1% for glimepiride plus metformin.
No episodes of major hypoglycaemia were reported in trials with the combination therapy plus metformin, and no subject discontinued the study treatment due to hypoglycaemia.
Urinary Tract Infections: In the pooled safety analysis, urinary tract infections were balanced across the 3 treatment groups: 5.7% in the saxagliptin and 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: 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.
Necrotising fasciitis of the perineum (Fournier' gangrene): Dapagliflozin: In the dapagliflozin cardiovascular outcomes study with 17,160 patients with type 2 diabetes mellitus and a median exposure time of 48 months, a total of 6 cases of Fournier's gangrene were reported on treatment, one in the dapagliflozin-treated group and 5 in the placebo group.
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: 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 and 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 and 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.
Cardiovascular Safety: In the pool of three studies,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.
No cardiovascular outcomes studies have been conducted to evaluate the saxagliptin/dapagliflozin combination.
In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction (SAVOR) Trial, an increase in the rate of hospitalisation for heart failure was observed in the saxagliptin-treated patients compared to placebo, although a causal relationship has not been established.
In the Dapagliflozin Effect on Cardiovascular Events (DECLARE) study, a reduced risk of hospitalisation for heart failure was observed in the dapagliflozin treated patients compared to placebo.
The overall effect of QTERN on hospitalisation for heart failure in adults with type 2 diabetes mellitus is unknown.
Vital signs: 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: 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.