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In the previously described trials, the frequency of AEs leading to discontinuation was similar by treatment groups for placebo (5.6%), JARDIANCE 10 mg (5.0%) and JARDIANCE 25 mg (5.3%).
Placebo-controlled double-blind trials of 18 to 24 weeks of exposure included 3534 patients, of which 1183 were treated with placebo, 1185 were treated with JARDIANCE 10 mg and 1166 were treated with JARDIANCE 25 mg (see Table 10).
The most frequent adverse drug reaction was hypoglycaemia, which depended on the type of background therapy used in the respective studies (see Table 11.)
Click on icon to see table/diagram/imageHypoglycaemia: The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for JARDIANCE and placebo as monotherapy, as add-on to metformin, 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 JARDIANCE compared to placebo when given as add-on to metformin plus sulfonylurea, and as add-on to insulin +/- metformin and +/-sulfonylurea. (see Table 11.)
Major hypoglycaemia (events requiring assistance): The frequency of patients with major hypoglycaemic events was low (<1%) and similar for JARDIANCE and placebo as monotherapy, as add-on to metformin +/-sulfonylurea, as add on to pioglitazone +/- metformin. The frequency of patients with major hypoglycaemic events was increased in patients treated with JARDIANCE compared to placebo when given as add-on to insulin +/- metformin and +/-sulfonylurea.
Click on icon to see table/diagram/imageUrinary tract infection: The overall frequency of urinary tract infection adverse events was similar in patients treated with JARDIANCE 25 mg and placebo (7.0% and 7.2%), and higher in patients treated with JARDIANCE 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for JARDIANCE in patients with a history of chronic or recurrent urinary tract infections. The intensity of urinary tract infections was similar to placebo for mild, moderate, and severe intensity reports. Urinary tract infection events were reported more frequently for empagliflozin compared to placebo in female patients, but not in male patients.
Vaginal moniliasis, vulvovaginitis, balanitis and other genital infection: Vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for JARDIANCE 10 mg (4.0%) and JARDIANCE 25 mg (3.9%) compared to placebo (1.0%). These adverse events were reported more frequently for empagliflozin compared to placebo in female patients, and the difference in frequency was less pronounced in male patients. The 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 JARDIANCE 10 mg (3.5%) and JARDIANCE 25 mg (3.3%) compared to placebo (1.4%). Increased urination was mostly mild or moderate in intensity. The frequency of reported nocturia was comparable between placebo and JARDIANCE (<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 similar to placebo (JARDIANCE 10 mg 0.6%, JARDIANCE 25 mg 0.4% and placebo 0.3%). The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients aged 75 years and older. In patients ≥75 years of age (pooling of all patients with diabetes, n=13,402) the frequency of volume depletion events was similar for JARDIANCE 10 mg (2.3%) compared to placebo (2.1%), but it increased with JARDIANCE 25 mg (4.3%).
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 (blood creatinine increased: JARDIANCE 10 mg 0.6%, JARDIANCE 25 mg 0.1%, placebo 0.5%; glomerular filtration rate decreased: empagliflozin 10 mg 0.1%, empagliflozin 25 mg 0%, placebo 0.3%).
In placebo-controlled, double-blind studies up to 76 weeks, initial transient increases in creatinine (mean change from baseline after 12 weeks: JARDIANCE 10 mg 0.0011 mmol/L, JARDIANCE 25 mg 0.0006 mmol/L) and initial transient decreases in estimated glomerular filtration rates (mean change from baseline after 12 weeks: JARDIANCE 10 mg-1.34mL/min/1.73m2, JARDIANCE 25 mg-1.37mL/min/1.73m2) have been observed. These changes were generally reversible during continuous treatment or after drug discontinuation (see Pharmacology: Clinical Trials: Cardiovascular outcome: Figure 4 for the eGFR course in the EMPA-REG OUTCOME study under Actions).
Laboratory parameters: Haematocrit increased: In a pooled safety analysis (pooling of all patients with diabetes, n=13,402), mean changes from baseline in haematocrit were 3.4% and 3.6% for empagliflozin 10 mg and 25 mg, respectively, compared to -0.1% for placebo. In the EMPA-REG OUTCOME study, haematocrit values returned towards baseline values after a follow-up period of 30 days after treatment stop.
Serum lipids increased: In a pooled safety analysis (pooling of all patients with diabetes, n=13,402), mean percent increases from baseline for empagliflozin 10 mg and 25 mg versus placebo, respectively, were total cholesterol 4.9% and 5.7% versus 3.5%; HDL-cholesterol 3.3% and 3.6% versus 0.4%; LDL-cholesterol 9.5% and 10.0% versus 7.5%; triglycerides 9.2% and 9.9% versus 10.5%.
Postmarketing experience: Ketoacidosis, Urosepsis, Pyelonephritis, Allergic skin reactions (e.g. rash, urticaria).
