ADVERSE REACTIONS
The safety of concomitantly administered linagliptin and metformin has been evaluated in more than 2800 patients with type 2 diabetes mellitus treated for >12 weeks in clinical trials.
Adverse Reactions Reported in ≥5% of Patients with Linagliptin/Metformin and Greater than with Placebo in a 24-week Factorial-Design Study
| PLACEBO (%) n=72 |
LINAGLIPTIN (%) n=142 |
METFORMIN MONOTHERAPY (%) n=291 |
COMBINATION OF LINAGLIPTIN + METFORMIN (%) n=286 |
|
|---|---|---|---|---|
| Nasopharyngitis | 1.4 | 5.6 | 2.7 | 6.3 |
| Diarrhea | 2.8 | 3.5 | 3.8 | 6.3 |
|
Nasopharyngitis PLACEBO (%) n=72 1.4 LINAGLIPTIN (%) n=142 5.6 METFORMIN MONOTHERAPY (%) n=291 2.7 COMBINATION OF LINAGLIPTIN + METFORMIN (%) n=286 6.3 |
|---|
|
Diarrhea PLACEBO (%) n=72 2.8 LINAGLIPTIN (%) n=142 3.5 METFORMIN MONOTHERAPY (%) n=291 3.8 COMBINATION OF LINAGLIPTIN + METFORMIN (%) n=286 6.3 |
Other adverse reactions reported in clinical studies with the treatment of linagliptin/metformin were hypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity), cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.
- Other adverse reactions reported in clinical studies with treatment of linagliptin monotherapy were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia
- Adverse reactions reported in ≥2% of patients treated with linagliptin 5 mg and more commonly than in patients with placebo included: Nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3% vs 3.0%), and cough (2.1% vs 1.4%)
- In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient-years of exposure while being treated with linagliptin compared with 3.7 cases per 10,000 patient-years of exposure while being treated with comparator (placebo and active comparator, sulfonylurea). Three additional cases of pancreatitis were reported following the last administered dose of linagliptin
- The most common adverse reactions due to initiation of metformin are diarrhea, nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort, and headache
- Long-term treatment with metformin has been associated with a decrease in vitamin B12 absorption, which may very rarely result in clinically significant vitamin B12 deficiency (e.g., megaloblastic anemia)
Linagliptin/Metformin
- In a 24-week factorial-design study, hypoglycemia was reported in 4 (1.4%) of 286 subjects treated with linagliptin/metformin, 6 (2.1%) of 291 subjects treated with metformin, and 1 (1.4%) of 72 subjects treated with placebo
- When linagliptin was administered in combination with metformin and a sulfonylurea, 181 (22.9%) of 792 patients reported hypoglycemia compared with 39 (14.8%) of 263 patients administered placebo in combination with metformin and sulfonylurea
Linagliptin
- In the study of patients receiving linagliptin as add-on therapy to a stable dose of insulin for up to 52 weeks, no significant difference in the incidence of investigator-reported hypoglycemia was noted compared with placebo (31.4% vs 32.9%, respectively)
- In a study of linagliptin compared with placebo as add-on to pre-existing antidiabetic therapy in patients with severe renal impairment, the incidence of hypoglycemia was higher in patients treated with linagliptin (63%) vs in patients treated with placebo (49%). Severe hypoglycemic events were reported in 4.4% of patients treated with linagliptin vs 4.6% of patients treated with placebo in this trial
Linagliptin
- Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the linagliptin group and ≥1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the linagliptin group)
- Increase in Lipase: In a placebo-controlled clinical trial with linagliptin in type 2 diabetes mellitus patients with micro- or macroalbuminuria, a mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the linagliptin arm compared to a mean decrease of 2% in the placebo arm. Lipase levels above 3 times upper limit of normal were seen in 8.2% compared to 1.7% patients in the linagliptin and placebo arms, respectively
