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 Jardiance 10 mg/day (n=2345), 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 (5.3%), JARDIANCE 10 mg (4.8%) and JARDIANCE 25 mg (4.9%).
Placebo controlled double-blind trials of 18 to 24 weeks of exposure included 3,534 patients, of which 1,183 were treated with placebo, 1,185 were treated with JARDIANCE 10 mg and 1,166 were treated with 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 (HF): 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 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 JARDIANCE and placebo as monotherapy, 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 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; see Table 24 as follows).
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, and 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 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 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%), 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.
Cases of phimosis/acquired phimosis have been reported concurrent with genital infections.
Standard care and treatment should be exercised when having vaginal moniliasis, vulvovaginitis, balanitis and other genital infections.
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, 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: 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 Figure 6 on Pharmacology: Clinical Trials under Actions for the eGFR course in the EMPA-REG outcome study).
Clinical Trial in Pediatric Patients Aged 10 to 17 Years with Type 2 Diabetes Mellitus: JARDIANCE was administered to 52 patients in a trial of 157 pediatric patients aged 10 to 17 years with type 2 diabetes mellitus with a mean exposure to JARDIANCE of 23.8 weeks [see Pharmacology: Clinical Trials under Actions].
The risk of hypoglycemia was higher in pediatric patients treated with JARDIANCE regardless of concomitant insulin use. Hypoglycemia, defined as a blood glucose <54 mg/dL, occurred in 10 (19.2%) patients and in 4 (7.5%) patients treated with JARDIANCE and placebo, respectively. No severe hypoglycemic events occurred (severe hypoglycemia was defined as an event requiring the assistance of another person to actively administer carbohydrates, glucagon or take other corrective actions).