A total of 12245 patients with type 2 diabetes were treated in clinical studies to evaluate the safety of empagliflozin plus metformin, of which 8199 patients were treated with empagliflozin plus metformin, either alone, or in addition to a sulfonylurea, pioglitazone, DPP4 inhibitors, or insulin. In these trials 2910 patients received treatment with empagliflozin 10 mg plus metformin and 3699 patients treatment with empagliflozin 25 mg plus metformin for at least 24 weeks and 2151 or 2807 patients for at least 76 weeks.
The overall safety profile of empagliflozin plus metformin for patients enrolled in the EMPA-REG OUTCOME study was comparable to the previously known safety profile.
Placebo-controlled, double-blind trials of 18 to 24 weeks of exposure included 3456 patients, of which 1271 were treated with empagliflozin 10 mg plus metformin and 1259 with empagliflozin 25 mg plus metformin.
The most frequently reported adverse event in clinical trials was hypoglycaemia, which depended on the type of background therapy used in the respective studies (see Description of selected adverse reactions as follows).
No additional adverse reactions were identified in clinical trials with empagliflozin plus metformin compared to the adverse reactions of the single components.
Tabulated list of adverse reactions: The adverse reactions are listed by absolute frequency. Frequencies 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), or very rare (<1/10,000), and not known (cannot be estimated from the available data). (See Table 15.)
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Description of selected adverse reactions: The frequencies as follows are calculated for adverse reactions regardless of causality.
Hypoglycaemia: The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar to placebo for empagliflozin as add-on to metformin and as add-on to pioglitazone +/- metformin, and as add-on with linagliptin + metformin. The frequency of patients with hypoglycaemia was increased in patients treated with empagliflozin compared to placebo when given as add-on to metformin plus sulfonylurea, and as add-on to insulin +/- metformin and +/-sulfonylurea. (see Dosage & Administration; see Table 16 as follows).
Major hypoglycaemia (events requiring assistance): The overall frequency of patients with major hypoglycaemic events was low (<1%) and similar for empagliflozin and placebo on a background of metformin.
The frequency of major hypoglycaemia depended on the background therapy in the respective studies (see Dosage & Administration; see Table 16 as follows). (See Table 16.)
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Urinary tract infection: The overall frequency of urinary tract infection adverse events was higher in patients treated with empagliflozin 10 mg plus metformin (8.8%) as compared to empagliflozin 25 mg plus metformin (6.6%) or placebo plus metformin (7.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin plus metformin in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections was similar to placebo. Urinary tract infection events were reported more frequently for empagliflozin 10 mg plus metformin compared with placebo in female patients, but not for empagliflozin 25 mg plus metformin. The frequencies of urinary tract infections were low for male patients and were balanced across treatment groups.
Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection: Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for empagliflozin 10 mg plus metformin (4.0%) and empagliflozin 25 mg plus metformin (3.9%) compared to placebo plus metformin (1.3%), and were reported more frequently for empagliflozin plus metformin compared to placebo in female patients. The difference in frequency was less pronounced in male patients. Genital tract infections were mild and moderate in intensity, none was severe in intensity.
Increased urination: As expected via its mechanism of action, increased urination (as assessed by PT search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients treated with empagliflozin 10 mg plus metformin (3.0%) and empagliflozin 25 mg plus metformin (2.9%) compared to placebo plus metformin (1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and empagliflozin, both on a background of metformin (<1%).
Volume depletion: The overall frequency of volume depletion (including the predefined terms blood pressure (ambulatory) decreased, blood pressure systolic decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension, and syncope) was low and comparable to placebo (empagliflozin 10 mg plus metformin (0.6%), empagliflozin 25 mg plus metformin (0.3%) and placebo plus metformin (0.1%). The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect the hydration status of patients aged 75 years and older. In patients ≥75 years of age, volume depletion events have been reported in a single patient treated with empagliflozin 25 mg plus metformin.
Blood creatinine increased and glomerular filtration rate decreased: The overall frequency of patients with increased blood creatinine and decreased glomerular filtration rate was similar between empagliflozin and placebo as add-on to metformin (blood creatinine increased: empagliflozin 10 mg 0.5%, empagliflozin 25 mg 0.1%, placebo 0.4%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.2%).
In these placebo-controlled, double-blind studies up to 24 weeks, initial transient increases in creatinine (mean change from baseline after 12 weeks: empagliflozin 10 mg 0.02 mg/dL, empagliflozin 25 mg 0.02 mg/dL) and initial transient decreases in estimated glomerular filtration rates (mean change from baseline after 12 weeks: empagliflozin 10 mg -1.46 mL/min/1.73m2, empagliflozin 25 mg -2.05 mL/min/1.73m2) have been observed. In the long term studies, these changes were generally reversible during continuous treatment or after drug discontinuation (see Figure 6 in Pharmacology: Pharmacodynamics: Clinical Trials under Actions for the eGFR course in the EMPA-REG outcome study).
Inform the doctor or pharmacist immediately about side effects that occur while taking the drug.