Rhea Dapagliflozin Adverse Reactions

Clinical Trials: The safety profile of dapagliflozin has been evaluated in clinical development programs for type 2 diabetes mellitus, type 1 diabetes mellitus, heart failure and chronic kidney disease. This includes more than 15000 subjects treated with dapagliflozin for type 2 diabetes, more than 1000 subjects treated with dapagliflozin for type 1 diabetes, more than 2000 subjects treated with dapagliflozin for heart failure, and more than 2000 subjects treated with dapagliflozin for chronic kidney disease. 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 type 2 diabetes patients that included 1145 patients treated with dapagliflozin 5 mg (mean exposure = 22 weeks) and 1393 patients treated with placebo (mean exposure = 21 weeks), either as monotherapy or in combination with other antidiabetic therapies.
In the dedicated cardiovascular (CV) outcomes study in patients with type 2 diabetes mellitus (DECLARE), 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.
In the dapagliflozin cardiovascular outcome study in patients with heart failure with reduced ejection fraction (DAPA-HF), 2368 patients were treated with dapagliflozin 10 mg and 2368 patients with placebo for a median exposure time of 18 months. The patient population included patients with type 2 diabetes mellitus and without diabetes, and patients with eGFR ≥30 mL/min/1.73 m².
In the dapagliflozin renal outcome study in patients with chronic kidney disease (DAPA-CKD), 2149 patients were treated with dapagliflozin 10 mg and 2149 patients with placebo for a median exposure of 27 months. The patient population included patients with type 2 diabetes mellitus and without diabetes, with eGFR ≥25 and ≤75 mL/min/1.73 m². Treatment was continued if eGFR fell to levels below 25 mL/min/1.73 m².
The safety profile of dapagliflozin was overall consistent across the studied indications. DKA was observed only in patients with diabetes mellitus.
Adverse reactions: The adverse reactions in patients treated with Dapagliflozin 10 mg in clinical trials and postmarketing, are shown in Table 15. (See Table 15.)

Click on icon to see table/diagram/image

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 versus 0% in placebo). Infections were more frequently reported in females (8.4% Dapagliflozin 10 mg vs. 1.2% placebo) than in males (3.4% Dapagliflozin 10 mg versus 0.2% placebo). The most frequently reported genital infections were vulvovaginal mycotic infections in females, and balanitis in males.
In the DECLARE 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.
In the DAPA-HF study, no patient reported a SAE of genital infections in the dapagliflozin group and one in the placebo group. There were 7 (0.3%) patients with adverse events leading to discontinuations (DAE) due to genital infections in the dapagliflozin group and none in the placebo group.
In the DAPA-CKD study, there were 3 (0.1%) patients with SAE of genital infections in the dapagliflozin group and none in the placebo group. There were 3 (0.1%) patients with DAEs due to genital infections in the dapagliflozin group and none in the placebo group.
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 versus 0.1% placebo). Infections were more frequently reported in females (8.5% Dapagliflozin 10 mg versus 6.7% placebo) than in males (1.8% Dapagliflozin 10 mg versus 1.3% placebo).
In the DECLARE 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.
In the DAPA-HF study, the number of patients with SAEs of UTI were low and balanced: 14 (0.6%) patients in the dapagliflozin group and 17 (0.7%) patients in the placebo group. There were 5 (0.2%) patients with DAEs due to urinary tract infections in each of the dapagliflozin and placebo groups.
In the DAPA-CKD study, there were 29 (1.3%) patients with SAEs of UTI in the dapagliflozin group and 18 (0.8%) patients in the placebo group. There were 8 (0.4%) patients with DAEs due to urinary tract infections in the dapagliflozin group and 3 (0.1%) in the placebo group.
Diabetic ketoacidosis (DKA): Type 2 diabetes mellitus: In the DECLARE 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).
In the DAPA-HF study, events of DKA were reported in 3 patients with type 2 diabetes mellitus in the dapagliflozin group and none in the placebo group.
In the DAPA-CKD study, events of DKA were not reported in any patient in the dapagliflozin group and in 2 patients with type 2 diabetes mellitus in the placebo group.
Necrotizing 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.