Glyxambi Adverse Reactions

A total of 2173 patients with type 2 diabetes were treated in clinical studies to evaluate the safety of Empagliflozin + Linagliptin (GLYXAMBI), of which 1005 patients were treated with Empagliflozin + Linagliptin (GLYXAMBI). In clinical trials, patients were treated for up to 24 or 52 weeks.
The most frequent adverse reaction was urinary tract infection (see Description of selected adverse reactions as follows).
Overall, the safety profile of Empagliflozin + Linagliptin (GLYXAMBI) was comparable to the safety profiles of the individual components (empagliflozin and linagliptin).
The adverse reactions shown in Table 5 listed by system organ class, are based on the safety profiles of empagliflozin and linagliptin monotherapy, and were also reported in clinical trials and post marketing surveillance with Empagliflozin + Linagliptin (GLYXAMBI). No additional adverse reactions were identified with Empagliflozin + Linagliptin (GLYXAMBI) as compared to the individual components. (See Table 5.)

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Description of selected adverse reactions: The frequencies as follows are calculated for adverse reactions regardless of causality.
Hypoglycaemia: In pooled clinical trials of Empagliflozin + Linagliptin (GLYXAMBI) in patients with type 2 diabetes and inadequate glycaemic control on background metformin, the incidence of confirmed hypoglycaemic events was low (<1.5%; for confirmed clinical events per trial see Table 6).
One patient administered Empagliflozin + Linagliptin (GLYXAMBI) experienced a confirmed (investigator-defined), major hypoglycaemic event in the active- or placebo-controlled trials and none required assistance. (See Table 6.)

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Hypoglycaemia for empagliflozin: The frequency of hypoglycaemia depended on the background therapy in the respective studies and was similar for empagliflozin and placebo as monotherapy, as add-on to metformin, and as add-on to pioglitazone +/- 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.
Major hypoglycaemia with empagliflozin (events requiring assistance): The frequency of patients with major hypoglycaemic events was low (<1%) and similar for empagliflozin and placebo as monotherapy, as add-on to metformin +/- sulfonylurea, and as add-on to pioglitazone +/- metformin.
The frequency of patients with major hypoglycaemic events was increased in patients treated with empagliflozin compared to placebo when given as add-on to insulin +/- metformin and +/- sulfonylurea.
Hypoglycaemia with linagliptin: The most frequently reported adverse event in clinical trials with linagliptin was hypoglycaemia observed under the triple combination, linagliptin plus metformin plus sulphonylurea (22.9% vs 14.8% in placebo).
Hypoglycaemias in the placebo-controlled studies (10.9%; N=471) were mild (80%; N=384) or moderate (16.6%; N=78) or severe (1.9%; N=9) in intensity.
Urinary tract infection: In clinical trials with Empagliflozin + Linagliptin (GLYXAMBI), the frequency of urinary tract infection adverse events (Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg: 9.2%; Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg: 8.8%) has been comparable to those reported from the empagliflozin clinical trials.
In empagliflozin trials, the overall frequency of urinary tract infection adverse events was similar in patients treated with empagliflozin 25 mg and placebo (7.0% and 7.2%), and higher in patients treated with empagliflozin 10 mg (8.8%). 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: In clinical trials with Empagliflozin + Linagliptin (GLYXAMBI), the frequency of genital infection adverse events (Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg: 3.1%; Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg: 3.5%) has been comparable to those reported from the empagliflozin clinical trials.
In empagliflozin trials, vaginal moniliasis, vulvovaginitis, balanitis and other genital infections were reported more frequently for empagliflozin 10 mg (4.0%) and empagliflozin 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: In clinical trials with Empagliflozin + Linagliptin (GLYXAMBI), the frequency of increased urination adverse events (Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg: 1.7%; Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg: 0.8%) has been comparable to those reported from the empagliflozin clinical trials.
As expected via its mechanism of action, in clinical trials with empagliflozin, increased urination (as assessed by PT search including pollakiuria, polyuria, nocturia) was observed at higher frequencies in patients treated with empagliflozin 10 mg (3.5%) and empagliflozin 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 (<1%).
Volume depletion: In clinical trials with Empagliflozin + Linagliptin (GLYXAMBI), the frequency of patients with volume depletion adverse events (Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg: 0.6%; Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg: 0.5%) has been comparable to those reported from the empagliflozin clinical trials.
In clinical trials with empagliflozin, the overall frequency of patients with volume depletion adverse events was similar to placebo (placebo 0.3%, empagliflozin 10 mg 0.6%, and empagliflozin 25 mg 0.4%). The effect of empagliflozin on urinary glucose excretion is associated with osmotic diuresis, which could affect hydration status of patients age 75 years and older. In patients ≥75 years of age the frequency of patients with volume depletion events was similar for empagliflozin 10 mg (2.3%) compared to placebo (2.1%), but it increased with empagliflozin 25 mg (4.3%).
Blood creatinine increased and glomerular filtration rate decreased: In clinical trials with Empagliflozin + Linagliptin (GLYXAMBI), the frequency of patients with increased blood creatinine (Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg: 0.4%; Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg: 0%) and decreased glomerular filtration rate (Empagliflozin + Linagliptin (GLYXAMBI) 25 mg/5 mg: 0.4%; Empagliflozin + Linagliptin (GLYXAMBI) 10 mg/5 mg: 0.6%) has been comparable to those reported from the empagliflozin clinical trials.
In clinical trials with empagliflozin, 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.