Sidapvia Adverse Reactions

Clinical Trials: The safety of the combined use of 10 mg dapagliflozin and 100 mg sitagliptin has been evaluated in a placebo-controlled Phase 3 clinical study of 48 weeks duration. In this study, a total of 225 patients with type 2 diabetes mellitus received dapagliflozin as add on therapy to sitagliptin (with or without metformin), and 226 received placebo plus sitagliptin (with or without metformin). No additional adverse reactions were identified for the combined use of dapagliflozin and sitagliptin compared with those reported for the individual components (see Table 4).
The safety profile of dapagliflozin in type 2 diabetes mellitus has been evaluated in clinical studies including more than 15000 subjects treated with dapagliflozin. 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, including add on therapy to sitagliptin).
In the dedicated cardiovascular (CV) outcomes study with dapagliflozin 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.
Adverse drug reactions: The adverse drug reactions in patients treated with dapagliflozin 10 mg (with or without other antidiabetic medications, including add-on therapy to sitagliptin) and sitagliptin (as monotherapy) in clinical trials are shown in Table 4. Adverse drug reactions are organised by MedDRA System Organ Class (SOC). Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000) and not known (cannot be estimated from available data). (See Table 4.)

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Post-marketing experience: The adverse drug reactions identified during post-marketing experience with the individual mono-components are shown in Table 5. Because these reactions are reported voluntarily from a population of an uncertain size, it is not always possible to reliably estimate their frequency. Adverse drug reactions are organised by MedDRA System Organ Class (SOC). Frequencies of occurrence of adverse reactions are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10000 to <1/1000); very rare (<1/10000) and not known (cannot be estimated from available data). (See Table 5.)

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Description of selected adverse reactions: Genital infections: Dapagliflozin: In the dapagliflozin added-on to sitagliptin (with or without metformin) study, events of genital infections were reported in 9.3% of the patients in the dapagliflozin group and 0.4% in the placebo group.
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 reported more frequently in females (8.4% dapagliflozin 10 mg versus 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.
Urinary tract infections: Dapagliflozin: In the dapagliflozin added-on to sitagliptin (with or without metformin) study, events of urinary tract infections (UTI) were reported in 5.8% of the patients in the dapagliflozin group and 3.5% in the placebo group.
Events of 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.
Diabetic ketoacidosis (DKA): Dapagliflozin: 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).
Hypoglycaemia: Dapagliflozin: The incidence of hypoglycaemia as seen in the dapagliflozin added on to sitagliptin (with or without metformin) study and in the DECLARE study is shown in Table 6. (See Table 6.)

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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.
Sitagliptin: Hypoglycaemia was observed more frequently (frequency 'very common') when sitagliptin was studied with the combination of sulphonylurea and metformin, compared with studies of sitagliptin as monotherapy.
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7332 patients treated with sitagliptin, 100 mg daily (or 50 mg daily if the baseline eGFR was ≥30 and <50 mL/min/1.73 m²), and 7339 patients treated with placebo in the intention to treat population. Among patients who were using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 2.7% in sitagliptin-treated patients and 2.5% in placebo-treated patients; among patients who were not using insulin and/or a sulfonylurea at baseline, the incidence of severe hypoglycaemia was 1.0% in sitagliptin-treated patients and 0.7% in placebo treated patients.
Acute pancreatitis: Sitagliptin: In the TECOS study, the incidence of adjudication-confirmed pancreatitis events was 0.3% in sitagliptin-treated patients and 0.2% in placebo treated patients.