QTERN Adverse Reactions

Clinical trials: Safety profile of saxagliptin/dapagliflozin combination: 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 clinical trials for up to 52 weeks (see Pharmacology: Pharmacodynamics under Actions). The 3-study pooled safety analysis of 1169 adults is referred in this document as pooled safety analysis: saxagliptin and dapagliflozin plus metformin (492 subjects; data pooled from 3 studies CV181169, CV181168, and MB102129); saxagliptin plus metformin (336 subjects data pooled from studies CV181169 and MB102129); and dapagliflozin plus metformin (341 subjects data pooled from studies CV181169 and CV181168).
Tabulated list of adverse reactions for saxagliptin/dapagliflozin combination: The adverse reactions are presented in Table 10. The adverse reactions are listed by system organ class (SOC) and absolute frequency.
Common frequency for Table 10 is defined as ≥2% to <10% and very common frequency as ≥10%. (See Table 10.)

Click on icon to see table/diagram/image

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 (DECLARE).
Additional clinical trials for up to 52 weeks in adult subjects compared the combination therapy of saxagliptin 5 mg and dapagliflozin 10 mg plus metformin to active/placebo comparators of basal insulin, sitagliptin, 1-6 mg glimepiride (a sulphonylurea), with all comparator arms on a background of ≥1,500 mg metformin. The safety results for these studies continue to demonstrate that the combination of saxagliptin and dapagliflozin plus metformin is well-tolerated and is consistent with the known safety profiles for the pooled safety analysis of saxagliptin 5 mg and dapagliflozin 10 mg combination plus metformin, and its monocomponents.
Postmarketing experience: Saxagliptin: During postmarketing experience, the following adverse reactions have been reported with use of saxagliptin: acute pancreatitis, arthralgia, bullous pemphigoid and hypersensitivity reactions, including anaphylaxis, angioedema, rash, and urticaria. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.
Dapagliflozin: During postmarketing experience, the following adverse reactions have been reported with use of dapagliflozin. (See Table 11.)

Click on icon to see table/diagram/image

Description of selected adverse reactions: Genital infections: The reported adverse events of vulvovaginitis, balanitis and related genital infections from pooled safety analysis were reflective of the safety profile of dapagliflozin. AEs of genital infection were reported in 3.0% in the saxagliptin and 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.
Urinary tract infections: In the pooled safety analysis, UTIs 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 UTI), and were mild or moderate in intensity, of single occurrence, and most patients continued on therapy.
Diabetic ketoacidosis (DKA): In a large cardiovascular outcomes study with dapagliflozin in patients with type 2 diabetes (DECLARE), 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).
Laboratory findings: Decrease in lymphocyte count: Saxagliptin: In a pool of 5 placebo-controlled studies, a small mean decrease in absolute lymphocyte count was observed, approximately 100 cells/microL relative to placebo. Mean absolute lymphocyte counts remained stable with daily dosing up to 102 weeks in duration. The decrease in mean absolute lymphocyte count was not associated with clinically relevant adverse reactions.
Lipids: Data from the saxagliptin and dapagliflozin plus metformin treatment arms of 3 Phase 3 trials, demonstrated trends of mean percent increases from baseline in Total-C, (ranging from 0.4% to 3.8%), LDL-C (ranging from 2.1 to 6.9%), and HDL-C (ranging 2.3 to 5.4%) along with mean percent decreases from baseline in triglycerides (ranging from -3.0% to -10.8%).