Xigduo XR Adverse Reactions

Clinical trials: Dapagliflozin + metformin: Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin coadministered with metformin immediate- or extended-release was used to evaluate safety data. This pool included several add-on studies (metformin alone and in combination with a DPP4 inhibitor and metformin, or insulin and metformin), 2 initial combination with metformin studies, and 2 studies of patients with cardiovascular disease (CVD) and type 2 diabetes who received their usual treatment (with metformin as background therapy). For studies that included background therapy with and without metformin, only patients who received metformin were included in the 8-study placebo-controlled pool. Across these 8 studies 983 patients were treated once daily with dapagliflozin 10 mg and metformin and 1185 were treated with placebo and metformin. These 8 studies provide a mean duration of exposure of 23 weeks. The mean age of the population was 57 years and 2% were older than 75 years. Fifty-four percent (54%) of the population was male; 88% White, 6% Asian, and 3% Black or African American. At baseline, the population had diabetes for an average of 8 years, mean hemoglobin A1c (HbA1c) was 8.4%, and renal function was normal or mildly impaired in 90% of patients and moderately impaired in 10% of patients.
The most commonly reported events leading to discontinuation and reported in at least 3 patients treated with dapagliflozin 10 mg and metformin were renal impairment (0.7%), increased blood creatinine (0.2%), decreased renal creatinine clearance (0.2%), and urinary tract infection (0.2%).
Dapagliflozin: The safety profile of dapagliflozin in type 2 diabetes mellitus has been evaluated in clinical studies including more than 15,000 subjects treated with dapagliflozin. For further information about the clinical studies, see Pharmacology: Pharmacodynamics under Actions.
The incidence of adverse reactions was determined using a pre-specified pool of patients from 13 short-term (mean duration 22 weeks), placebo-controlled studies in type 2 diabetes. Across these 13 studies, 2360 patients were treated once daily with dapagliflozin 10 mg and 2295 were treated with placebo (either as monotherapy or in combination with other antidiabetic therapies).
Additionally, dapagliflozin 5 mg was evaluated in a 12-study, short-term, placebo-controlled pool of patients that included 1145 patients treated with dapagliflozin 5 mg (mean exposure = 22 weeks) and 1393 patients treated (mean exposure = 21 weeks), either as monotherapy or in combination with other antidiabetic therapies.
The most commonly reported events leading to discontinuation and reported in at least 3 dapagliflozin 10 mg-treated patients were renal impairment (0.8%), decrease in creatinine clearance (0.6%), increased blood creatinine (0.3%), urinary tract infections (0.2%), and vulvovaginal mycotic infection (0.1%).
Additional adverse reactions in ≥5% of patients treated with dapagliflozin 10 mg, ≥1% more than patients in placebo/comparator, and reported in at least three more patients treated with dapagliflozin 10 mg and regardless of relationship to dapagliflozin reported by investigator, were reviewed by treatment regimen. The only study with a metformin treatment component meeting these criteria was: add-on to metformin: headache (5.3% dapagliflozin 10 mg and 3.1% placebo).
In the dedicated cardiovascular (CV) outcomes study in patients with type 2 diabetes mellitus, 8574 patients received dapagliflozin 10 mg and 8569 received placebo for a median exposure time of 48 months. In total, there were 30623 patient-years of exposure to dapagliflozin.
Adverse reactions: The adverse reactions in patients treated with dapagliflozin 10 mg with and without metformin in clinical trials in type 2 diabetes mellitus and post marketing are shown in Table 13. (See Table 13.)

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Clinical trial data and post-marketing data - metformin hydrochloride: Table 14 presents adverse reactions by system organ class and by frequency category. (See Table 14.)

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Description of selected adverse reactions: Genital Infections: Events of genital infections were reported in 5.5% and 0.6% of patients who received dapagliflozin 10 mg and placebo, respectively, in the 13-study, short-term, placebo-controlled pool. The events of genital infections reported in patients treated with dapagliflozin 10 mg were all mild to moderate. Most events of genital infection responded to an initial course of standard treatment and rarely resulted in discontinuation from the study (0.2% dapagliflozin 10 mg vs 0% in placebo). Infections were reported more frequently in females (8.4% dapagliflozin 10 mg vs 1.2% placebo) than in males (3.4% dapagliflozin 10 mg vs 0.2% placebo). The most frequently reported genital infections were vulvovaginal mycotic infections in females, and balanitis in males.
In the CV outcomes study, the number of patients with serious adverse events (SAE) of genital infections were few and balanced: 2 (<0.1%) patients in each of the dapagliflozin and placebo groups.
Urinary Tract Infections: Events of urinary tract infections (UTI) were reported in 4.7% and 3.5% of patients who received dapagliflozin 10 mg and placebo, respectively, in the 13-study, short-term, placebo-controlled pool. Most events of urinary tract infections reported in patients treated with dapagliflozin 10 mg were mild to moderate. Most patients responded to an initial course of standard treatment, and urinary tract infections rarely caused discontinuation from the study (0.2% dapagliflozin 10 mg vs 0.1% placebo). Infections were more frequently reported in females (8.5% dapagliflozin 10 mg vs 6.7% placebo) than in males (1.8% dapagliflozin 10 mg vs 1.3% placebo).
In the CV outcomes study there were fewer patients with SAEs of UTI in the dapagliflozin group compared with the placebo group: 79 (0.9%) and 109 (1.3%), respectively.
Diabetic ketoacidosis (DKA): In the CV outcomes study 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).
Necrotising fasciitis of the perineum (Fournier's gangrene): Cases of Fournier's gangrene have been reported postmarketing in patients taking SGLT2 inhibitors, including dapagliflozin (see Precautions).
In the dapagliflozin cardiovascular outcomes study with 17,160 type 2 diabetes mellitus patients and a median exposure time of 48 months, a total of 6 cases of Fournier's gangrene were reported, one in the dapagliflozin-treated group and 5 in the placebo group.