e
†AUC = AUC(INF) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments
**AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic endpoints
INR = International Normalized Ratio
PT = Prothrombin Time
QD = once daily
BID = twice daily
TID = three times daily
Metformin 850 mg TID 10 mg QD metformin 1.01 0.89
Glyburide 1.75 mg# 5 mg QD glyburide 0.86 0.86
Pioglitazone 45 mg QD 10 mg QD pioglitazone
metabolite M-III
metabolite M-IV 0.94
0.98
1.04 0.86
0.96
1.05
Digoxin 0.25 mg QD 5 mg QD digoxin 1.02 0.94
Simvastatin 40 mg QD 10 mg QD simvastatin
simvastatin acid 1.34
1.33 1.10
1.21
Warfarin 10 mg# 5 mg QD R-warfarin
S-warfarin
INR
PT 0.99
1.03
0.93**
1.03** 1.00
1.01
1.04**
1.15**
Ethinylestradiol and levonorgestrel ethinylestradiol 0.03 mg and
levonorgestrel 0.150 mg QD 5 mg QD ethinylestradiol
levonorgestrel 1.01
1.09 1.08
1.13
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Linagliptin did not increase the incidence of tumors in male and female rats in a 2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of 60 mg/kg is approximately 418 times the clinical dose of 5 mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in a 2-year study at doses up to 80 mg/kg (males) and 25 mg/kg (females), or approximately 35- and 270-times the clinical dose based on AUC exposure. Higher doses of linagliptin in female mice (80 mg/kg) increased the incidence of lymphoma at approximately 215-times the clinical dose based on AUC exposure.
Linagliptin was not mutagenic or clastogenic with or without metabolic activation in the Ames bacterial mutagenicity assay, a chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay.
In fertility studies in rats, linagliptin had no adverse effects on early embryonic development, mating, fertility, or bearing live young up to the highest dose of 240 mg/kg (approximately 943 times the clinical dose based on AUC exposure).
14 CLINICAL STUDIES
TRADJENTA has been studied as monotherapy and in combination with metformin, glimepiride, and pioglitazone therapy. TRADJENTA has not been studied in combination with insulin.
There were approximately 3800 patients with type 2 diabetes randomized in 8 double-blind, placebo-controlled clinical safety and efficacy studies conducted to eva luate the effects of linagliptin on glycemic control. The overall ethnic/racial distribution in these studies was approximately 65% White, 33% Asian, and 2% Black, and included 14% Hispanic/Latino patients. Fifty-two percent of patients were male. Patients had an overall mean age of 57 years (range 20 to 80 years). In addition, an active (glimepiride)-controlled study of 52-weeks duration was conducted in over 1500 patients with type 2 diabetes who had inadequate glycemic control on metformin.
In patients with type 2 diabetes, treatment with TRADJENTA produced clinically significant improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG) compared with placebo.
14.1 Monotherapy
A total of 730 patients with type 2 diabetes participated in 2 double-blind, placebo-controlled studies, one of 18-week and another of 24-week duration, to eva luate the efficacy and s
