Sidapvia Adverse Reactions

Significant adverse events are also described in Precautions.
The adverse events with SIDAPVIA are consistent with the adverse events for each component. For further information on adverse effects associated with dapagliflozin and sitagliptin components, refer to the appropriate individual Product Information document.
Clinical trials: Dapagliflozin/sitagliptin fixed-dose combination tablets have been demonstrated to be bioequivalent with co-administered dapagliflozin and sitagliptin. In therapeutic clinical trials, dapagliflozin and sitagliptin were administered as individual tablets.
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 15,000 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, 2,360 patients were treated once daily with dapagliflozin 10 mg, and 2,295 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), 8,574 patients received dapagliflozin 10 mg and 8,569 received placebo for a median exposure time of 48 months. In total, there were 30,623 patient-years of exposure to dapagliflozin.
Adverse drug reactions: The adverse drug reactions in patients treated with dapagliflozin 10 mg (with or without other anti-diabetic 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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from available data). (See Table 4.)

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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. In both groups, the events were mild or moderate in intensity and more common in female than male patients.
In the pooled analysis of 13 short-term, placebo-controlled studies, events of genital infections were reported in 5.5% and 0.6% of patients who received dapagliflozin 10 mg and placebo, respectively. 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). Subjects with a history of recurrent genital infection were more likely to experience an infection. 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 9 of the 13 studies in the placebo-controlled pool, long-term data was available. In this short-term plus long-term placebo-pooled analysis (mean duration of treatment was 439.5 days for dapagliflozin 10 mg and 419.0 days for placebo); the proportions of patients with events of genital infections were 7.7% (156/2,026) in the dapagliflozin 10 mg group and 1.0% (19/1,956) in the placebo group. Of the patients treated with dapagliflozin 10 mg who experienced an infection, 67.9% had only one and 10.9% had 3 or more. Of the patients treated with placebo who experienced an infection, 89.5% had only one and none had 3 or more.
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. There were 74 and 7 patients with non-serious adverse events of genital infections leading to study drug discontinuation in the dapagliflozin group and placebo group, respectively.
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 DELIVER study, one (<0.1%) patient in each treatment group reported a SAE of genital infections. There were 3 (0.1%) patients with DAEs due to genital infection 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: 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, and more commonly in females.
In the pooled analysis of 13 short-term, placebo-controlled studies, events of UTI were reported in 4.7% and 3.5% of patients who received dapagliflozin 10 mg and placebo, respectively. 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). Subjects with a history of recurrent urinary tract infection were more likely to experience an infection. 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) (see Precautions).
In the short-term plus long-term placebo-pooled analysis of 9 short-term studies with long-term data available, the proportions of patients with events of urinary tract infections were 8.6% in the dapagliflozin 10 mg group and 6.2% in the placebo group. Of the patients treated with dapagliflozin 10 mg who experienced an infection, 77.6% had only one and 6.3% had 3 or more. Of the patients treated with placebo who experienced an infection, 77.7% had only one and 9.9% had 3 or more.
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.
The number of patients with SAEs of UTI were low and balanced in the DAPA-HF and DELIVER studies: in DAPA-HF, there were 14 (0.6%) patients in the dapagliflozin group and 17 (0.7%) in the placebo group and in DELIVER there were 41 (1.3%) patients in the dapagliflozin group and 37 (1.2%) in the placebo group. In the DAPA-HF study, there were 5 (0.2%) patients with DAEs due to UTI in each of the dapagliflozin and placebo groups. In the DELIVER study, there were 13 (0.4%) patients with DAEs due to UTI in the dapagliflozin group and 9 (0.3%) in the placebo group.
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 UTI in the dapagliflozin group and 3 (0.1%) in the placebo group.
Diabetic ketoacidosis (DKA): Dapagliflozin: In the DECLARE study with dapagliflozin in patients with type 2 diabetes, where 8,574 patients received dapagliflozin 10 mg and 8,569 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).
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 5. (See Table 5.)

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Sitagliptin: In a pre-specified pooled analysis of two monotherapy studies, an add-on to metformin study, and an add-on to pioglitazone study, the overall incidence of adverse experiences of hypoglycaemia in patients treated with sitagliptin 100 mg was similar to placebo (1.2% vs. 0.9%). Adverse experiences of hypoglycaemia were based on all reports of hypoglycaemia; a concurrent glucose measurement was not required.
The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) included 7,332 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 7,339 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.
Pancreatitis: Sitagliptin: In a pooled analysis of 19 double-blind clinical trials that included data from 10,246 patients randomised to receive sitagliptin 100 mg/day (N=5,429) or corresponding (active or placebo) control (N=4,817), the incidence of non-adjudicated acute pancreatitis events was 0.1 per 100 patient-years in each group (4 patients with an event in 4,708 patient-years for sitagliptin and 4 patients with an event in 3,942 patient-years for control) (see Pancreatitis under Precautions).
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.
Volume depletion: Dapagliflozin: In the pooled analysis of 13 short-term, placebo-controlled studies, events suggestive of volume depletion (including reports of dehydration, hypovolemia, or hypotension) were reported in 1.1% and 0.7% of patients who received dapagliflozin 10 mg and placebo, respectively. Across the pool of 21 active and placebo-controlled studies, serious events occurred in ≤0.2% of patients and were balanced between dapagliflozin 10 mg and comparator (see Precautions).
Adverse events of volume depletion were more commonly seen in patients with moderate renal impairment.
In the cardiovascular outcomes study, the number of patients with events suggestive of volume depletion were balanced between treatment groups: 213 (2.5%) and 207 (2.4%) in the dapagliflozin and placebo groups, respectively. Serious adverse events were reported in 81 (0.9%) and 70 (0.8%) in the dapagliflozin and placebo group, respectively. Events were generally balanced between treatment groups across subgroups of age, diuretic use, blood pressure and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use. In patients with eGFR <60 mL/min/1.73 m² at baseline, there were 19 events of serious adverse events suggestive of volume depletion in 604 patients in the dapagliflozin group and 13 events in 658 patients in the placebo group.
Necrotising fasciitis of the perineum (Fournier's 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.
Events related to decreased renal function: Dapagliflozin: Use of dapagliflozin was associated with increases in serum creatinine and decreases in eGFR. These changes were observed to reverse after treatment discontinuation, suggesting acute haemodynamic changes play a role in the renal function abnormalities observed with dapagliflozin.
In the 13-study, short-term, placebo-controlled pool, mean serum creatinine levels increased a small amount at Week 1 (mean change from baseline: 0.0036 mmol/L dapagliflozin 10 mg versus 0.0007 mmol/L placebo) and decreased toward baseline by Week 24 (mean change from baseline: 0.019 mg/dL dapagliflozin 10 mg versus 0.008 mg/dL placebo). There were no further changes through Week 102.
In the cardiovascular outcomes study, there were fewer patients with marked laboratory abnormalities of creatinine, creatinine clearance, eGFR, and urine albumin to creatinine ratio (UACR) in the dapagliflozin group compared with the placebo group. Fewer renal events (e.g., decreased renal creatinine clearance, renal impairment, increased blood creatinine, and decreased glomerular filtration rate) were reported in the dapagliflozin group compared with the placebo group: 422 (4.9%) and 526 (6.1%), respectively. There were fewer patients with events reported as acute kidney injury in the dapagliflozin group compared with the placebo group: 125 (1.5%) and 175 (2.0%), respectively. There were fewer patients with SAEs of renal events in the dapagliflozin group compared with the placebo group: 80 (0.9%) and 136 (1.6%), respectively. eGFR decreased over time in both treatment groups. At 1 year, mean eGFR was slightly lower, and at 4 years, mean eGFR was slightly higher in the dapagliflozin group compared with the placebo group.
Post-marketing experience: The adverse drug reactions identified during post-marketing experience with the individual mono-components are shown in Table 6. 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 (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); and not known (cannot be estimated from available data). (See Table 6.)

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