Xigduo XR Adverse Reactions

Clinical experience: Dapagliflozin and metformin hydrochloride: Data from a prespecified pool of patients from 8 short-term, placebo-controlled studies of dapagliflozin co-administered 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 overall incidence of adverse events for the 8-study, short-term, placebo-controlled pool in patients treated with dapagliflozin 10 mg and metformin was 60.3% compared to 58.2% for the placebo and metformin group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg and metformin was 4% compared to 3.3% for the placebo and metformin group. 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%).
The adverse reactions in the 8-study, short-term, placebo-controlled pooled analysis reported (regardless of investigator assessment of causality) in ≥2% of patients treated with dapagliflozin 10 mg and metformin, and ≥1% more frequently than patients treated with placebo and metformin, are shown in Table 5. (See Table 5.)


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Dapagliflozin: Two major pools of patients were used to evaluate adverse reactions with dapagliflozin 10 mg versus control, a placebo-controlled study pool and a larger pool of active and placebo controlled studies.
Placebo-Controlled Studies: The first pool is a prespecified pool of patients from 13 short-term, placebo-controlled studies used to evaluate and present all safety data for dapagliflozin other than malignancies, liver tests, and hypoglycemia (evaluated by individual study). This pool included the monotherapy studies, several add-on studies (metformin, sulfonylurea, pioglitazone, DPP4 inhibitor, insulin, and two studies with a combination of add-on therapies), and an initial combination with metformin study. 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).
These 13 studies provide a mean duration of exposure of 22 weeks. The mean age of the population was 59 years and 4% were older than 75 years. Fifty-eight percent (58%) of the population was male; 84% were White, 9% were Asian, and 3% were Black or African American. At baseline, the population had diabetes for an average of 9 years, mean HbA1c was 8.2%, and renal function was normal or mildly impaired in 88% of patients and moderately impaired in 11% of patients.
Active- and Placebo-Controlled Studies: The second pool is a pool of patients from 21 active- and placebo-controlled studies used to evaluate and present data for malignancies and liver tests. In this pool, 5936 patients were treated with dapagliflozin and 3403 were treated with control (either as monotherapy or in combination with other antidiabetic therapies).
These 21 studies provide a mean duration of exposure to dapagliflozin 10 mg of 55 weeks (6247 patient-years). Across both treatment groups, the mean age of the population was 58 years and 3.5% were older than 75 years. Fifty-six percent (56%) of the population was male; 77% were White, 16% were Asian, and 4% were Black or African American. At baseline, the population had diabetes for an average of 7 years, 34% of patients had a history of cardiovascular disease, mean HbA1c was 8.2%, and baseline renal function was normal or mildly impaired in 89% of patients and moderately impaired in 11% of patients.
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 as monotherapy or in combination with other antidiabetic therapy (mean exposure=22 weeks) and 1393 patients treated with placebo as monotherapy or in combination with other antidiabetic therapy (mean exposure=21 weeks). All safety data presented for dapagliflozin 5 mg is from this pool.
The overall incidence of adverse events for the 13-study, short-term, placebo-controlled pool (short-term treatment) in patients treated with dapagliflozin 10 mg was 60.0% compared to 55.7% for the placebo group. Discontinuation of therapy due to adverse events in patients who received dapagliflozin 10 mg was 4.3% compared to 3.6% for the placebo group. 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%).
The adverse reactions in this 13-study placebo-controlled pooled analysis reported (regardless of investigator assessment of causality) in ≥2% of patients treated with dapagliflozin 10 mg, and ≥1% more frequently than patients treated with placebo, are shown in Table 6. (See Table 6.)


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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 a dedicated study of patients with moderate renal impairment, 13 patients with an adverse event of bone fracture were reported up to Week 104, of which 8 occurred in the dapagliflozin 10 mg group. Eight (8) of these 13 fractures were in patients who had eGFR 30 to 45 mL/min/1.73 m² and 10 of the 13 fractures were reported within the first 52 weeks. There was no apparent pattern with respect to the site of fracture. At Week 52 and persisting through Week 104, greater increases in mean parathyroid hormone (PTH) and serum phosphorus were observed in this study for patients treated with dapagliflozin 10 mg compared with placebo, where baseline values of these analytes were higher.
Cardiovascular Outcomes Study (DECLARE): In the DECLARE study, [see Pharmacology: Pharmacodynamics: Clinical Trial Information under Actions], 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.
Volume depletion: Adverse reactions for the 12-study and 13-study, short-term, placebo-controlled pools and for the DECLARE study are shown in Table 7: (See Table 7.)


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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, in the 13-study, short-term, placebo-controlled pool. Serious events occurred in ≤0.2% of patients across 21 active- and placebo-controlled studies (dapagliflozin as monotherapy or in combination with other antidiabetic therapies) and were balanced between dapagliflozin 10 mg and comparator.
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 DECLARE study, the number of patients with serious adverse events of genital mycotic infections were few and balanced: 2 (<0.1%) patients in each of the dapagliflozin-treated and placebo groups.
Urinary Tract Infections: In the 13-study safety pool, urinary tract infections were more frequently reported for dapagliflozin compared with placebo (4.7% versus 3.5%, respectively; see Precautions). Most infections were mild to moderate, and subjects responded to an initial course of standard treatment and rarely resulted in discontinuation from dapagliflozin treatment. These infections were more frequent in females, and subjects with a prior history were more likely to have a recurrent infection.
In the dapagliflozin cardiovascular outcomes study, serious events of urinary tract infections were reported less frequently for dapagliflozin 10 mg compared with placebo, 79 (0.9%) events versus 109 (1.3%) events, respectively.
Hypoglycemia: In studies with dapagliflozin in add-on combination with metformin, minor episodes of hypoglycemia were reported at similar frequencies in the group treated with dapagliflozin 10 mg plus metformin (6.9%) and in the placebo plus metformin group (5.5%). No major events of hypoglycemia were reported.
In an add-on to metformin study up to 24 weeks, minor episodes of hypoglycemia were reported in 12.8% of subjects who received dapagliflozin 10 mg plus metformin and in 3.7% of subjects who received placebo plus metformin. No major events of hypoglycemia were reported. (See Table 8.)


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Events Related to Decreased Renal Function: In the 13-study, short-term, placebo-controlled pool, reported terms referring to events related to decreased renal function were grouped (e.g., decreased renal creatinine clearance, renal impairment, increased blood creatinine, and decreased glomerular filtration rate). This group of events was reported in 3.2% and 1.8% of patients who received dapagliflozin 10 mg and placebo, respectively. In patients with normal renal function or mild renal impairment (baseline eGFR ≥60 mL/min/1.73m²) events related to decreased renal function were reported in 1.3% and 0.8% of patients who received dapagliflozin 10 mg and placebo, respectively.
Events related to decreased renal function were more common in patients with baseline eGFR ≥30 and <60 mL/min/1.73m² (18.5% dapagliflozin 10 mg vs. 9.3% placebo).
Further evaluation of patients who had renal-related adverse events showed that most had serum creatinine changes of ≤44 μmol/L from baseline. The increases in creatinine were generally transient during continuous treatment or reversible after discontinuation of treatment.
Data from the DECLARE study showed that long-term exposure (up to 60 months) to dapagliflozin 10 mg, including elderly patients and patients with renal impairment (eGFR less than 60 mL/min/1.73 m²), was not associated with an increased risk for renal-related adverse events. There were fewer patients with marked laboratory abnormalities of creatinine, creatinine clearance, eGFR, and urine albumin to creatinine ratio (UACR) in the dapagliflozin 10 mg treated group compared with the placebo group. eGFR decreased over time in both treatment groups (see Table 9).


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Ketoacidosis: In the DECLARE study with a median exposure time of 48 months, events of diabetic ketoacidosis (DKA) were reported in 27 patients in the dapagliflozin-treated group and 12 patients in the placebo group. The events were evenly distributed over the study period. Of the 27 patients with DKA events in the dapagliflozin-treated 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).
Monotherapy - metformin hydrochloride: The most common adverse reactions in placebo-controlled clinical trials reported in >5% of patients treated with metformin hydrochloride extended-release and more commonly than in placebo-treated patients included diarrhea and nausea/vomiting (both very common).
Laboratory findings: Hematocrit: Dapagliflozin: In the pool of 13 placebo-controlled studies, increases from baseline in mean hematocrit values were observed in dapagliflozin-treated patients starting at Week 1 and continuing up to Week 16, when the maximum mean difference from baseline was observed. At Week 24, the mean changes from baseline in hematocrit were 2.30% in the dapagliflozin 10 mg group versus -0.33% in the placebo group. At Week 102, the mean changes were 2.68% versus -0.46%, respectively. By Week 24, hematocrit values >55% were reported in 1.3% of dapagliflozin 10- mg-treated patients versus 0.4% of placebo-treated patients. Results were similar during the short-term plus long-term phase (the majority of patients were exposed to treatment for more than one year).
Serum Inorganic Phosphorus: Dapagliflozin: In the pool of 13 placebo-controlled studies, increases from baseline in mean serum phosphorus levels were reported at Week 24 in dapagliflozin 10-mg-treated patients compared with placebo-treated patients (mean increases of 0.13 mg/dL vs. -0.04 mg/dL, respectively). Similar results were seen at Week 102. Higher proportions of patients with marked laboratory abnormalities of hyperphosphatemia (≥5.6 mg/dL if age 17-65 or ≥5.1 mg/dL if age ≥66) were reported in dapagliflozin 10 mg group versus placebo at Week 24 (1.7% vs. 0.9%, respectively) and during the short-term plus long-term phase (3.0% vs. 1.6%, respectively). The clinical relevance of these findings is unknown.
Lipids: Dapagliflozin: In the pool of 13 placebo-controlled studies, small changes from baseline in mean lipid values were reported at Week 24 in dapagliflozin-10-mg-treated patients compared with placebo treated patients. Mean percent change from baseline at Week 24 for dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.5% versus 0.0%; HDL cholesterol, 6.0% versus 2.7%; LDL cholesterol, 2.9% versus -1.0%; triglycerides, -2.7% versus -0.7%. Mean percent change from baseline at Week 102 for dapagliflozin 10 mg versus placebo, respectively, was as follows: total cholesterol, 2.1% versus -1.5%; HDL cholesterol, 6.6% versus 2.1%; LDL cholesterol, 2.9% versus -2.2%; triglycerides, -1.8% versus -1.8%. The ratio between LDL cholesterol and HDL cholesterol decreased for both treatment groups at Week 24. In the DECLARE study, mean changes from baseline after 4 years were 0.4 mg/dL versus - 4.1 mg/dL for total cholesterol, and -2.5 mg/dL versus -4.4 mg/dL for LDL cholesterol, in dapagliflozin 10 mg-treated and the placebo groups, respectively.
Vitamin B12 Levels: Metformin hydrochloride: In controlled clinical trials of metformin of 29-week duration, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation (see Precautions).
Postmarketing Experience: Dapagliflozin: Additional adverse reactions have been identified during postapproval use of dapagliflozin. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure: Ketoacidosis; Acute Kidney Injury and Impairment in Renal Function; Urosepsis and Pyelonephritis; Rash.
Metformin: Cholestatic, hepatocellular, and mixed hepatocellular liver injury.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions to AstraZeneca.