Glyxambi Adverse Reactions

Adverse events in clinical trials: A total of 2173 patients with type 2 diabetes were treated in clinical studies to evaluate the safety of GLYXAMBI, of which 1005 patients were treated with 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 GLYXAMBI was comparable to the safety profiles of the individual components (empagliflozin and linagliptin).
The adverse reactions shown in Table 6 listed by system organ class, are based on the safety profiles of empagliflozin and linagliptin monotherapy, and were also reported in clinical trials and postmarketing surveillance with GLYXAMBI. No additional adverse reactions were identified with GLYXAMBI as compared to the individual 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 6.)

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Description of selected adverse reactions: The following frequencies are calculated for adverse reactions regardless of causality.
Hypoglycaemia: In pooled clinical trials of 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 7). One patient administered GLYXAMBI experienced a confirmed (investigator-defined), major hypoglycaemic event in the active- or placebo-controlled trials and none required assistance. (See Table 7.)

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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 sulfonylurea (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 GLYXAMBI, the frequency of urinary tract infection adverse events (GLYXAMBI 25 mg/5 mg: 9.2%; 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 was similar in patients treated with empagliflozin 25 mg (7.0%) and placebo (7.2%), and higher in patients treated with empagliflozin 10 mg (8.8%). Similar to placebo, urinary tract infection was reported more frequently for empagliflozin 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: In clinical trials with GLYXAMBI, the frequency of genital infection adverse events (GLYXAMBI 25 mg/5 mg: 3.1%; 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%). 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: In clinical trials with GLYXAMBI, the frequency of increased urination adverse events (GLYXAMBI 25 mg/5 mg: 1.7%; 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 preferred term 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 GLYXAMBI, the frequency of patients with volume depletion adverse events (GLYXAMBI 25 mg/5 mg: 0.6%; 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 (including the predefined terms BP (ambulatory) decreased, SBP decreased, dehydration, hypotension, hypovolaemia, orthostatic hypotension and syncope) was similar to placebo (0.6% for empagliflozin 10 mg, 0.4% for empagliflozin 25 mg and 0.3% for placebo). 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: Use of empagliflozin was associated with increases in serum creatinine and decreases in eGFR. These changes were observed to reverse after treatment discontinuation, suggesting acute haemodynamic changes play a role in the renal function abnormalities observed with empagliflozin.
Renal-related adverse reactions (e.g. acute kidney injury, renal impairment, acute prerenal failure) may occur in patients treated with empagliflozin.
In clinical trials with GLYXAMBI, the frequency of patients with increased blood creatinine (GLYXAMBI 25 mg/5 mg: 0.4%; GLYXAMBI 10 mg/5 mg: 0%) and decreased glomerular filtration rate (GLYXAMBI 25 mg/5 mg: 0.4%; GLYXAMBI 10 mg/5 mg: 0.6%) has been comparable to those reported from the empagliflozin clinical trials.
Laboratory parameters: Haematocrit increased: In clinical trials with GLYXAMBI, mean changes from baseline in haematocrit were 2.9% and 3.2% for GLYXAMBI 10 mg/5 mg and 25 mg/5 mg.
In the EMPA-REG OUTCOME trial, haematocrit values returned towards baseline values after a follow-up period of 30 days after treatment stop.
Serum lipids increased: In clinical trials with GLYXAMBI, mean percent increases from baseline for GLYXAMBI 10 mg/5 mg and 25 mg/5 mg respectively, were total cholesterol 3.0% and 3.4%; HDL cholesterol 6.8% and 5.8%; LDL cholesterol 5.4% and 5.4%; triglycerides 2.7% and 4.2%.