Jardiance Adverse Reactions

Type 2 diabetes mellitus: A total of 15,582 patients with type 2 diabetes were treated in clinical studies to evaluate the safety of empagliflozin, of which 10,004 patients were treated with empagliflozin, either alone or in combination with metformin, a sulfonylurea, a PPARγ agonist, DPP4 inhibitors, or insulin. This pool includes the EMPA-REG OUTCOME study involving 7,020 patients at high cardiovascular risk (mean age 63.1 years, 9.3% patients at least 75 years old, 28.5% women) treated with Empagliflozin (Jardiance) 10 mg/day (n=2345), Empagliflozin (Jardiance) 25 mg/day (n=2342), or placebo (n=2333) up to 4.5 years. The overall safety profile of empagliflozin in this study was comparable to the previously known safety profile. In the previously described trials, the frequency of AEs leading to discontinuation was similar by treatment groups for placebo, Empagliflozin (Jardiance) 10 mg and Empagliflozin (Jardiance) 25 mg.
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 Empagliflozin (Jardiance) 10 mg and 1166 were treated with Empagliflozin (Jardiance) 25 mg.
The most frequent adverse drug reaction was hypoglycaemia, which depended on the type of background therapy used in the respective studies (see Description of selected adverse reactions as follows).
Heart failure: The EMPEROR studies included patients with heart failure and either reduced ejection fraction (N = 3726) or preserved ejection fraction (N = 5985) treated with 10 mg empagliflozin or placebo. Approximately half of the patients had type 2 diabetes mellitus.
The most frequent adverse drug reaction was volume depletion (empagliflozin 10 mg: 11.4%; placebo: 9.7%).
Chronic kidney disease: The EMPA-KIDNEY study included patients with chronic kidney disease (N = 6609) treated with 10 mg empagliflozin or placebo. About 44% of the patients had type 2 diabetes mellitus.
No new adverse reactions were identified in the EMPA-KIDNEY study.
The overall safety profile of Empagliflozin (Jardiance) was generally consistent across the studied indications. (See Table 23.)

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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 for Empagliflozin (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 Empagliflozin (Jardiance) compared to placebo when given as add-on to metformin plus sulfonylurea, and as add-on to insulin +/- metformin and +/-sulfonylurea. (See Dosage & Administration and Table 24 as follows.)
Major hypoglycaemia (events requiring assistance): The frequency of patients with major hypoglycaemic events was low (<1%) and similar for Empagliflozin (Jardiance) and placebo as monotherapy, as add-on to metformin +/- sulfonylurea, as add-on to pioglitazone +/- metformin, and as add-on with linagliptin + metformin.
The frequency of patients with major hypoglycaemic events was increased in patients treated with Empagliflozin (Jardiance) compared to placebo when given as add-on to insulin +/- metformin and +/-sulfonylurea. (See Table 24.)

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Urinary tract infection: The overall frequency of urinary tract infection adverse events was similar in patients treated with Empagliflozin (Jardiance) 25 mg and placebo (7.0% and 7.2%), and higher in patients treated with Empagliflozin (Jardiance) 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for Empagliflozin (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 Empagliflozin (Jardiance) 10 mg (4.0%) and Empagliflozin (Jardiance) 25 mg (3.9%) compared to placebo (1.0%), and 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 Empagliflozin (Jardiance) 10 mg (3.5%) and Empagliflozin (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 Empagliflozin (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 (Empagliflozin (Jardiance) 10 mg 0.6%, Empagliflozin (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 Empagliflozin (Jardiance) 10 mg (2.3%) compared to placebo (2.1%), but it increased with Empagliflozin (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: empagliflozin 10 mg 0.6%, empagliflozin 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: empagliflozin 10 mg 0.02 mg/dL, empagliflozin 25 mg 0.01 mg/dL) and initial transient decreases in estimated glomerular filtration rates (mean change from baseline after 12 weeks: empagliflozin 10 mg -1.34 mL/min/1.73m², empagliflozin 25 mg -1.37 mL/min/1.73m²) have been observed. These changes were generally reversible during continuous treatment or after drug discontinuation (see Pharmacology: Pharmacodynamics: Clinical Trials: Figure 6 under Actions for the eGFR course in the EMPA-REG outcome study).