CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Glycemic Control Trials. TRADJENTA has been studied as monotherapy and in combination with metformin, sulfonylurea, pioglitazone, and insulin. TRADJENTA has also been studied in patients with type diabetes and severe chronic renal impairment.In patients with type 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.. MonotherapyA total of 730 patients with type diabetes participated in double-blind, placebo-controlled studies, one of 18 weeks and another of 24 weeks duration, to evaluate the efficacy and safety of TRADJENTA monotherapy. In both monotherapy studies, patients currently on an antihyperglycemic agent discontinued the agent and underwent diet, exercise, and drug washout period of about weeks that included an open-label placebo run-in during the last weeks. Patients with inadequate glycemic control (A1C 7% to 10%) after the washout period were randomized; patients not currently on antihyperglycemic agents (off therapy for at least weeks) with inadequate glycemic control (A1C 7% to 10%) were randomized after completing the 2-week, open-label, placebo run-in period. In the 18-week study, only patients ineligible for metformin were recruited. In the 18-week study, 76 patients were randomized to placebo and 151 to TRADJENTA mg; in the 24-week study, 167 patients were randomized to placebo and 336 to TRADJENTA mg. Patients who failed to meet specific glycemic goals during the 18-week study received rescue therapy with pioglitazone and/or insulin; metformin rescue therapy was used in the 24-week trial.Treatment with TRADJENTA mg daily provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 5). In the 18-week study, 12% of patients receiving TRADJENTA mg and 18% who received placebo required rescue therapy. In the 24-week study, 10.2% of patients receiving TRADJENTA mg and 20.9% of patients receiving placebo required rescue therapy. The improvement in A1C compared with placebo was not affected by gender, age, race, prior antihyperglycemic therapy, baseline BMI, or standard index of insulin resistance (HOMA-IR). As is typical for trials of agents to treat type diabetes, the mean reduction in A1C with TRADJENTA appears to be related to the degree of A1C elevation at baseline. In these 18- and 24-week studies, the changes from baseline in A1C were -0.4% and -0.4%, respectively, for those given TRADJENTA, and 0.1% and 0.3%, respectively, for those given placebo. Change from baseline in body weight did not differ significantly between the groups.Table 5Glycemic Parameters in Placebo-Controlled Monotherapy Studies of TRADJENTA 18-Week Study 24-Week Study TRADJENTA mg Placebo TRADJENTA mg Placebo Full analysis population using last observation on study18-week study: Placebo, n=68; TRADJENTA, n=13624-week study: Placebo, n=147; TRADJENTA, n=30618-week study. HbA1c: ANCOVA model included treatment, reason for metformin intolerance and number of prior oral anti-diabetic medicine(s) (OADs) as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment, reason for metformin intolerance and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.24-week study. HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as covariate.A1C (%)Number of patientsn 147n 73n 333n 163Baseline (mean)8.18.18.08.0Change from baseline (adjusted mean)-0.40.1-0.40.3Difference from placebo (adjusted mean) (95% CI)-0.6 (-0.9, -0.3)---0.7 (-0.9, -0.5)--Patients [n (%)] achieving A1C <7% 32 (23.5)8 (11.8)77 (25)17 (12)FPG (mg/dL)Number of patientsn 138n 66n 318n 149Baseline (mean)178176164166Change from baseline (adjusted mean)-137-915Difference from placebo (adjusted mean) (95% CI)-21 (-31, -10)---23 (-30, -16)--2-hour PPG (mg/dL)Number of patientsData not availableData not availablen 67n 24Baseline (mean)----258244Change from baseline (adjusted mean)-----3425Difference from placebo (adjusted mean) (95% CI)-----58 (-82, -34)--. Add-on Combination Therapy with MetforminA total of 701 patients with type diabetes participated in 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with metformin. Patients already on metformin (n 491) at dose of at least 1500 mg per day were randomized after completing 2-week, open-label, placebo run-in period. Patients on metformin and another antihyperglycemic agent (n 207) were randomized after run-in period of approximately weeks on metformin (at dose of at least 1500 mg per day) in monotherapy. Patients were randomized to the addition of either TRADJENTA mg or placebo, administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with glimepiride rescue.In combination with metformin, TRADJENTA provided statistically significant improvements in A1C, FPG, and 2-hour PPG compared with placebo (Table 6). Rescue glycemic therapy was used in 7.8% of patients treated with TRADJENTA mg and in 18.9% of patients treated with placebo. similar decrease in body weight was observed for both treatment groups.Table 6Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Metformin TRADJENTA mg MetforminPlacebo MetforminFull analysis population using last observation on studyTRADJENTA mg Metformin, n=485; Placebo Metformin, n=163HbA1c: ANCOVA model included treatment and number of prior oral OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. PPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline postprandial glucose after two hours as covariate.A1C (%) Number of patientsn 513n 175Baseline (mean)8.18.0Change from baseline (adjusted mean)-0.50.15Difference from placebo metformin (adjusted mean) (95% CI)-0.6 (-0.8, -0.5)--Patients [n (%)] achieving A1C <7% 127 (26.2)15 (9.2)FPG (mg/dL)Number of patientsn 495n 159Baseline (mean)169164Change from baseline (adjusted mean)-1111Difference from placebo metformin (adjusted mean) (95% CI)-21 (-27, -15)--2-hour PPG (mg/dL)Number of patientsn 78n 21Baseline (mean)270274Change from baseline (adjusted mean)-4918Difference from placebo metformin (adjusted mean) (95% CI)-67 (-95, -40)--. Initial Combination Therapy with MetforminA total of 791 patients with type diabetes mellitus and inadequate glycemic control on diet and exercise participated in the 24-week, randomized, double-blind, portion of this placebo-controlled factorial study designed to assess the efficacy of TRADJENTA as initial therapy with metformin. Patients on an antihyperglycemic agent (52%) underwent drug washout period of weeks duration. After the washout period and after completing 2-week single-blind placebo run-in period, patients with inadequate glycemic control (A1C >=7.0% to <=10.5%) were randomized. Patients with inadequate glycemic control (A1C >=7.5% to <11.0%) not on antihyperglycemic agents at study entry (48%) immediately entered the 2-week, single-blind, placebo run-in period and then were randomized. Randomization was stratified by baseline A1C (<8.5% vs >=8.5%) and use of prior oral antidiabetic drug (none vs monotherapy). Patients were randomized in 1:2:2:2:2:2 ratio to either placebo or one of active-treatment arms. Approximately equal numbers of patients were randomized to receive initial therapy with mg of TRADJENTA once daily, 500 mg or 1000 mg of metformin twice daily, or 2.5 mg of linagliptin twice daily in combination with 500 mg or 1000 mg of metformin twice daily. Patients who failed to meet specific glycemic goals during the study were treated with sulfonylurea, thiazolidinedione, or insulin rescue therapy.Initial therapy with the combination of linagliptin and metformin provided significant improvements in A1C and fasting plasma glucose (FPG) compared to placebo, to metformin alone, and to linagliptin alone (Table 7).The adjusted mean treatment difference in A1C from baseline to week 24 (LOCF) was -0.5% (95% CI -0.7, -0.3; p<0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to metformin 1000 twice daily; -1.1% (95% CI -1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin 1000 mg twice daily compared to TRADJENTA mg once daily; -0.6% (95% CI -0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to metformin 500 mg twice daily; and -0.8% (95% CI -1.0, -0.6; p<0.0001) for linagliptin 2.5 mg/metformin 500 mg twice daily compared to TRADJENTA mg once daily.Lipid effects were generally neutral. No meaningful change in body weight was noted in any of the treatment groups.Table 7Glycemic Parameters at Final Visit (24-Week Study) for Linagliptin and Metformin, Alone and in Combination in Randomized Patients with Type Diabetes Mellitus Inadequately Controlled on Diet and Exercise PlaceboTRADJENTA mg Once Daily Metformin 500 mg Twice DailyLinagliptin 2.5 mg Twice Daily Metformin 500 mg Twice DailyMetformin 1000 mg Twice DailyLinagliptin 2.5 mg Twice Daily Metformin 1000 mg Twice DailyTotal daily dose of TRADJENTA is equal to mgFull analysis population using last observation on studyMetformin 500 mg twice daily, n=140; Linagliptin 2.5 mg twice daily Metformin 500 twice daily, n=136; Metformin 1000 mg twice daily, n=137; Linagliptin 2.5 mg twice daily Metformin 1000 mg twice daily, n=138HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.A1C (%)Number of patientsn 65n 135n 141n 137n 138n 140Baseline (mean)8.78.78.78.78.58.7Change from baseline (adjusted mean)0.1-0.5-0.6-1.2-1.1-1.6Difference from placebo (adjusted mean) (95% CI)---0.6 (-0.9, -0.3)-0.8 (-1.0, -0.5)-1.3 (-1.6, -1.1)-1.2 (-1.5, -0.9)-1.7 (-2.0, -1.4)Patients [n (%)] achieving A1C <7% (10.8)14 (10.4)26 (18.6)41 (30.1)42 (30.7)74 (53.6)Patients (%) receiving rescue medication29.211.113.57.38.04.3FPG (mg/dL)Number of patientsn 61n 134n 136n 135n 132n 136Baseline (mean)203195191199191196Change from baseline (adjusted mean)10-9-16-33-32-49Difference from placebo (adjusted mean) (95% CI)---19 (-31, -6)-26 (-38, -14)-43 (-56, -31)-42 (-55, -30)-60 (-72, -47). Active-Controlled Study vs Glimepiride in Combination with MetforminThe efficacy of TRADJENTA was evaluated in 104-week, double-blind, glimepiride-controlled, non-inferiority study in patients with type diabetes with insufficient glycemic control despite metformin therapy. Patients being treated with metformin only entered run-in period of weeks duration, whereas patients pretreated with metformin and one additional antihyperglycemic agent entered run-in treatment period of weeks duration with metformin monotherapy (dose of >=1500 mg/day) and washout of the other agent. After an additional 2-week placebo run-in period, those with inadequate glycemic control (A1C 6.5% to 10%) were randomized 1:1 to the addition of TRADJENTA mg once daily or glimepiride. Randomization was stratified by baseline HbA1c (<8.5% vs >=8.5%), and the previous use of antidiabetic drugs (metformin alone vs metformin plus one other OAD). Patients receiving glimepiride were given an initial dose of mg/day and then electively titrated over the next 12 weeks to maximum dose of mg/day as needed to optimize glycemic control. Thereafter, the glimepiride dose was to be kept constant, except for down-titration to prevent hypoglycemia.After 52 and 104 weeks, TRADJENTA and glimepiride both had reductions from baseline in A1C (52 weeks: -0.4% for TRADJENTA, -0.6% for glimepiride; 104 weeks: -0.2% for TRADJENTA, -0.4% for glimepiride) from baseline mean of 7.7% (Table 8). The mean difference between groups in A1C change from baseline was 0.2% with 2-sided 97.5% confidence interval (0.1%, 0.3%) for the intent-to-treat population using last observation carried forward. These results were consistent with the completers analysis.Table 8Glycemic Parameters at 52 and 104 Weeks in Study Comparing TRADJENTA to Glimepiride as Add-On Therapy in Patients Inadequately Controlled on Metformin Week 52Week 104TRADJENTA mg MetforminGlimepiride Metformin(mean Glimepiride dose mg)TRADJENTA mg MetforminGlimepiride Metformin(mean Glimepiride dose mg)p<0.0001 vs glimepiride; +p=0.0012 vs glimepirideFull analysis population using last observation on studyHypoglycemic incidence included both asymptomatic events (not accompanied by typical symptoms and plasma glucose concentration of <=70 mg/dL) and symptomatic events with typical symptoms of hypoglycemia and plasma glucose concentration of <=70 mg/dL.HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates. Hypoglycemia incidence (%): Cochran-Mantel-Haenszel test was performed on the patient population contained in the treated set, to compare the proportion of patients with hypoglycemic events between patients treated with linagliptin and patients treated with glimepiride.A1C (%)Number of patientsn 764n 755n 764n 755Baseline (mean)7.77.77.77.7Change from baseline (adjusted mean)-0.4-0.6-0.2-0.4Difference from glimepiride (adjusted mean) (97.5% CI)0.2 (0.1, 0.3)--0.2 (0.1, 0.3)--FPG (mg/dL)Number of patientsn 733n 725n 733n 725Baseline (mean)164166164166Change from baseline (adjusted mean)-8 -15-2+ -9Hypoglycemia incidence (%) Number of patientsn 776n 775n 776n 775Incidence 5.3 31.17.5 36.1Patients treated with linagliptin had mean baseline body weight of 86 kg and were observed to have an adjusted mean decrease in body weight of 1.1 kg at 52 weeks and 1.4 kg at 104 weeks. Patients on glimepiride had mean baseline body weight of 87 kg and were observed to have an adjusted mean increase from baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104 weeks (treatment difference p<0.0001 for both timepoints).. Add-On Combination Therapy with PioglitazoneA total of 389 patients with type diabetes participated in 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with pioglitazone. Therapy was stopped in patients on oral antihyperglycemic therapy for period of weeks (4 weeks followed by 2-week, open-label, placebo run-in period). Drug-naive patients entered directly into the 2-week placebo run-in period. After the run-in period, patients were randomized to receive either TRADJENTA mg or placebo, both in addition to pioglitazone 30 mg daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured were A1C and FPG.In initial combination with pioglitazone 30 mg, TRADJENTA mg provided statistically significant improvements in A1C and FPG compared to placebo with pioglitazone (Table 9). Rescue therapy was used in 7.9% of patients treated with TRADJENTA mg/pioglitazone 30 mg and 14.1% of patients treated with placebo/pioglitazone 30 mg. Patient weight increased in both groups during the study with an adjusted mean change from baseline of 2.3 kg and 1.2 kg in the TRADJENTA mg/pioglitazone 30 mg and placebo/pioglitazone 30 mg groups, respectively (p 0.0141).Table 9Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination Therapy with Pioglitazone TRADJENTA mg PioglitazonePlacebo PioglitazoneFull analysis population using last observation on studyHbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.A1C (%) Number of patientsn 252n 128Baseline (mean)8.68.6Change from baseline (adjusted mean)-1.1-0.6Difference from placebo pioglitazone (adjusted mean) (95% CI)-0.5 (-0.7, -0.3)--Patients [n (%)] achieving A1C <7%108 (42.9)39 (30.5)FPG (mg/dL) Number of patientsn 243n 122Baseline (mean)188186Change from baseline (adjusted mean)-33-18Difference from placebo pioglitazone (adjusted mean) (95% CI)-14 (-21, -7)--. Add-On Combination with SulfonylureasA total of 245 patients with type diabetes participated in an 18-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with sulfonylurea (SU). Patients on sulfonylurea monotherapy (n 142) were randomized after completing 2-week, single-blind, placebo run-in period. Patients on sulfonylurea plus one additional oral antihyperglycemic agent (n 103) were randomized after wash-out period of weeks and 2-week, single-blind, placebo run-in period. Patients were randomized to the addition of TRADJENTA mg or to placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the studies were treated with metformin rescue. Glycemic endpoints measured included A1C and FPG.In combination with sulfonylurea, TRADJENTA provided statistically significant improvements in A1C compared with placebo following 18 weeks treatment; the improvements in FPG observed with TRADJENTA were not statistically significant compared with placebo (Table 10). Rescue therapy was used in 7.6% of patients treated with TRADJENTA mg and 15.9% of patients treated with placebo. There was no significant difference between TRADJENTA and placebo in body weight.Table 10Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Sulfonylurea TRADJENTA mg SUPlacebo SUSU sulfonylureaFull analysis population using last observation on studyTRADJENTA mg SU, n=156; Placebo SU, n=82HbA1c: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariatesA1C (%) Number of patientsn 158n 82Baseline (mean)8.68.6Change from baseline (adjusted mean)-0.5-0.1Difference from placebo SU (adjusted mean) (95% CI)-0.5 (-0.7, -0.2)--Patients [n (%)] achieving A1C <7% 23 (14.7)3 (3.7)FPG (mg/dL) Number of patientsn 155n 78Baseline (mean)180171Change from baseline (adjusted mean)-8-2Difference from placebo SU (adjusted mean) (95% CI)-6 (-17, 4)--. Add-On Combination Therapy with Metformin and SulfonylureaA total of 1058 patients with type diabetes participated in 24-week, randomized, double-blind, placebo-controlled study designed to assess the efficacy of TRADJENTA in combination with sulfonylurea and metformin. The most common sulfonylureas used by patients in the study were: glimepiride (31%), glibenclamide (26%), and gliclazide (26%, not available in the United States). Patients on sulfonylurea and metformin were randomized to receive TRADJENTA mg or placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue. Glycemic endpoints measured included A1C and FPG.In combination with sulfonylurea and metformin, TRADJENTA provided statistically significant improvements in A1C and FPG compared with placebo (Table 11). In the entire study population (patients on TRADJENTA in combination with sulfonylurea and metformin), mean reduction from baseline relative to placebo in A1C of -0.6% and in FPG of -13 mg/dL was seen. Rescue therapy was used in 5.4% of patients treated with TRADJENTA mg and in 13% of patients treated with placebo. Change from baseline in body weight did not differ significantly between the groups.Table 11Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Metformin and Sulfonylurea TRADJENTA mg Metformin SUPlacebo Metformin SUSU sulfonylureaFull analysis population using last observation on studyTRADJENTA mg Metformin SU, n=742; Placebo Metformin SU, n=247HbA1c: ANCOVA model included treatment as class-effects and baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.A1C (%) Number of patientsn 778n 262Baseline (mean)8.28.1Change from baseline (adjusted mean)-0.7-0.1Difference from placebo (adjusted mean) (95% CI)-0.6 (-0.7, -0.5)--Patients [n (%)] achieving A1C <7% 217 (29.2)20 (8.1)FPG (mg/dL) Number of patientsn 739n 248Baseline (mean)159163Change from baseline (adjusted mean)-58Difference from placebo (adjusted mean) (95% CI)-13 (-18, -7)--. Add-On Combination Therapy with InsulinA total of 1261 patients with type diabetes inadequately controlled on basal insulin alone or basal insulin in combination with oral drugs participated in randomized, double-blind, placebo-controlled trial designed to evaluate the efficacy of TRADJENTA as add-on therapy to basal insulin over 24 weeks. Randomization was stratified by baseline HbA1c (<8.5% vs >=8.5%), renal function impairment status (based on baseline eGFR), and concomitant use of oral antidiabetic drugs (none, metformin only, pioglitazone only, metformin pioglitazone). Patients with baseline A1C of >=7% and <=10% were included in the study including 709 patients with renal impairment (eGFR <90 mL/min), most of whom (n=575) were categorized as mild renal impairment (eGFR 60 to <90 mL/min). Patients entered 2 week placebo run-in period on basal insulin (e.g., insulin glargine, insulin detemir, or NPH insulin) with or without metformin and/or pioglitazone background therapy. Following the run-in period, patients with inadequate glycemic control were randomized to the addition of either mg of TRADJENTA or placebo, administered once daily. Patients were maintained on stable dose of insulin prior to enrollment, during the run-in period, and during the first 24 weeks of treatment. Patients who failed to meet specific glycemic goals during the double-blind treatment period were rescued by increasing background insulin dose.TRADJENTA used in combination with insulin (with or without metformin and/or pioglitazone), provided statistically significant improvements in A1C and FPG compared to placebo (Table 12) after 24 weeks of treatment. The mean total daily insulin dose at baseline was 42 units for patients treated with TRADJENTA and 40 units for patients treated with placebo. Background baseline diabetes therapy included use of: insulin alone (16.1%), insulin combined with metformin only (75.5%), insulin combined with metformin and pioglitazone (7.4%), and insulin combined with pioglitazone only (1%). The mean change from baseline to Week 24 in the daily dose of insulin was +1.3 IU in the placebo group and +0.6 IU in the TRADJENTA group. The mean change in body weight from baseline to Week 24 was similar in the two treatment groups.Table 12Glycemic Parameters in Placebo-Controlled Study for TRADJENTA in Combination with Insulin TRADJENTA mg InsulinPlacebo InsulinFull analysis population using last observation carried forward (LOCF) method on studyTRADJENTA Insulin, n=595; Placebo Insulin, n=593HbA1c: ANCOVA model included treatment, categorical renal function impairment status and concomitant OADs as class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment, categorical renal function impairment status and concomitant OADs as class-effects, as well as baseline HbA1c and baseline FPG as continuous covariates.A1C (%)Number of patientsn 618n 617Baseline (mean)8.38.3Change from baseline (adjusted mean)-0.60.1Difference from placebo (adjusted mean) (95% CI) -0.7 (-0.7, -0.6)--Patients [n (%)] achieving A1C <7% 116 (19.5)48 (8.1)FPG (mg/dL) Number of patientsn 613n 608Baseline (mean) 147151Change from baseline (adjusted mean)-83Difference from placebo (adjusted mean) (95% CI) -11 (-16, -6)--The difference between treatment with linagliptin and placebo in terms of adjusted mean change from baseline in HbA1c after 24 weeks was comparable for patients with no renal impairment (eGFR >=90 mL/min, n=539), with mild renal impairment (eGFR 60 to <90 mL/min, n= 565), or with moderate renal impairment (eGFR 30 to <60 mL/min, n=124).. Renal ImpairmentA total of 133 patients with type diabetes participated in 52 week, double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TRADJENTA in patients with both type diabetes and severe chronic renal impairment. Participants with an estimated (based on the four variables modified diet in renal disease [MDRD] equation) GFR value of <30 mL/min were eligible to participate in the study. Randomization was stratified by baseline HbA1c (<=8% and >8%) and background antidiabetic therapy (insulin or any combination with insulin, SU or glinides as monotherapy and pioglitazone or any other antidiabetics excluding any other DPP-4 inhibitors). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed. At baseline in this trial, 62.5% of patients were receiving insulin alone as background diabetes therapy, and 12.5% were receiving sulfonylurea alone.After 12 weeks of treatment, TRADJENTA mg provided statistically significant improvement in A1C compared to placebo, with an adjusted mean change of -0.6% compared to placebo (95% confidence interval -0.9, -0.3) based on the analysis using last observation carried forward (LOCF). With adjustments in antidiabetic background therapy after the initial 12 weeks, efficacy was maintained for 52 weeks, with an adjusted mean change from baseline in A1C of -0.7% compared to placebo (95% confidence interval -1.0, -0.4) based on analysis using LOCF.. 14.2 Cardiovascular Safety Trials. CARMELINAThe cardiovascular risk of TRADJENTA was evaluated in CARMELINA, multi-national, multi-center, placebo-controlled, double-blind, parallel group trial comparing TRADJENTA (N=3494) to placebo (N=3485) in adult patients with type diabetes mellitus and history of established macrovascular and/or renal disease. The trial compared the risk of major adverse cardiovascular events (MACE) between TRADJENTA and placebo when these were added to standard of care treatments for diabetes and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 2.2 years and vital status was obtained for 99.7% of patients.Patients were eligible to enter the trial if they were adults with type diabetes, with HbA1c of 6.5% to 10%, and had either albuminuria and previous macrovascular disease (39% of enrolled population), or evidence of impaired renal function by eGFR and Urinary Albumin Creatinine Ratio (UACR) criteria (42% of enrolled population), or both (18% of enrolled population).At baseline the mean age was 66 years and the population was 63% male, 80% Caucasian, 9% Asian, and 6% Black. Mean HbA1c was 8.0% and mean duration of type diabetes mellitus was 15 years. The trial population included 17% patients >=75 years of age and 62% patients with renal impairment defined as eGFR <60 mL/min/1.73 m2. The mean eGFR was 55 mL/min/1.73 m2 and 27% of patients had mild renal impairment (eGFR 60 to 90 mL/min/1.73 m2), 47% of patients had moderate renal impairment (eGFR 30 to <60 mL/min/1.73 m2) and 15% of patients had severe renal impairment (eGFR <30 mL/min/1.73 m2). Patients were taking at least one antidiabetic drug (97%), and the most common were insulin and analogues (57%), metformin (54%) and sulfonylurea (32%). Patients were also taking antihypertensives (96%), lipid lowering drugs (76%) with 72% on statin, and aspirin (62%).The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes which included cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The study was designed as non-inferiority trial with pre-specified risk margin of 1.3 for the hazard ratio of MACE.The results of CARMELINA, including the contribution of each component to the primary composite endpoint, are shown in Table 13. The estimated hazard ratio for MACE associated with TRADJENTA relative to placebo was 1.02 with 95% confidence interval of (0.89, 1.17). The upper bound of this confidence interval, 1.17, excluded the risk margin of 1.3. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 1.Table 13Major Adverse Cardiovascular Events (MACE) by Treatment Group in the CARMELINA TrialTRADJENTA mgn 3494Placebon 3485Hazard RatioNumber of Subjects (%)Incidence Rate per 1000 PY Number of Subjects (%)Incidence Rate per 1000 PY (95% CI)PY=patient yearsA patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcome.Composite of first event of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (MACE)434 (12.4)57.7420 (12.1)56.31.02 (0.89, 1.17)CV death 255 (7.3)32.6264 (7.6)34.00.96 (0.81, 1.14)Non-fatal MI 156 (4.5)20.6135 (3.9)18.01.15 (0.91, 1.45)Non-fatal stroke 65 (1.9)8.573 (2.1)9.60.88 (0.63, 1.23)Figure 1Kaplan-Meier: Time to First Occurrence of MACE in the CARMELINA Trial. Figure 1. CAROLINAThe cardiovascular risk of TRADJENTA was evaluated in CAROLINA, multi-center, multi-national, randomized, double-blind, parallel group trial comparing TRADJENTA (N=3023) to glimepiride (N=3010) in adult patients with type diabetes mellitus and history of established cardiovascular disease and/or multiple cardiovascular risk factors. The trial compared the risk of major adverse cardiovascular events (MACE) between TRADJENTA and glimepiride when these were added to standard of care treatments for diabetes and other cardiovascular risk factors. The trial was event driven, the median duration of follow-up was 6.23 years and vital status was obtained for 99.3% of patients.Patients were eligible to enter the trial if they were adults with type diabetes with insufficient glycemic control (defined as HbA1c of 6.5% to 8.5% or 6.5% to 7.5% depending on whether treatment-naive, on monotherapy or on combination therapy), and were defined to be at high cardiovascular risk with previous vascular disease, evidence of vascular related end-organ damage, age >=70 years, and/or two cardiovascular risk factors (duration of diabetes >10 years, systolic blood pressure >140 mmHg, current smoker, LDL cholesterol >=135 mg/dL).At baseline the mean age was 64 years and the population was 60% male, 73% Caucasian, 18% Asian, and 5% Black. The mean HbA1c was 7.15% and mean duration of type diabetes was 7.6 years. The trial population included 34% patients >=70 years of age and 19% patients with renal impairment defined as eGFR <60 mL/min/1.73 m2. The mean eGFR was 77 mL/min/1.73m2. Patients were taking at least one antidiabetic drug (91%) and the most common were metformin (83%) and sulfonylurea (28%). Patients were also taking antihypertensives (89%), lipid lowering drugs (70%) with 65% on statin, and aspirin (47%).The primary endpoint, MACE, was the time to first occurrence of one of three composite outcomes which included cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. The study was designed as non-inferiority trial with pre-specified risk margin of 1.3 for the upper bound of the 95% CI for the hazard ratio of MACE.The results of CAROLINA, including the contribution of each component to the primary composite endpoint, are shown in Table 14. The Kaplan-Meier curve depicting time to first occurrence of MACE is shown in Figure 2.Table 14Major Adverse Cardiovascular Events (MACE) by Treatment Group in the CAROLINA StudyTRADJENTA mg n=3023Glimepiride (1 mg to mg) n=3010Hazard RatioNumber of Subjects (%)Incidence Rate per 1000 PYNumber of Subjects (%)Incidence Rate per 1000 PY(95% CI)PY=patient yearsA patient may have experienced more than one component; therefore, the sum of the components is larger than the number of patients who experienced the composite outcomeComposite of first event of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke (MACE)356 (11.8)20.7362 (12.0)21.20.98 (0.84, 1.14)CV death169 (5.6)9.2168 (5.6)9.21.00 (0.81, 1.24)Non-fatal MI145 (4.8)8.3142 (4.7)8.21.01 (0.80, 1.28)Non-fatal stroke91 (3.0)5.2104 (3.5)6.00.87 (0.66, 1.15)Figure Time to First Occurrence of 3P-MACE in CAROLINA. Figure 2.

RENAL IMPAIRMENT SUBSECTION.

8.6 Renal Impairment. No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)]. In the TRADJENTA treatment arm of the CARMELINA trial [see Clinical Studies (14.2)], 2200 (63%) patients had renal impairment (eGFR <60 mL/min/1.73 m2). Approximately 20% of the population had eGFR >=45 to <60 mL/min/1.73 m2, 28% of the population had eGFR >=30 to <45 mL/min/1.73 m2 and 15% had eGFR <30 mL/min/1.73 m2. The overall incidence of adverse reactions were generally similar between the TRADJENTA and placebo treatment arms.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: March 2020 MEDICATION GUIDETRADJENTA(R) (TRAD gen ta)(linagliptin tablets)for oral useRead this Medication Guide carefully before you start taking TRADJENTA and each time you get refill. There may be new information. This information does not take the place of talking to your doctor about your medical condition or your treatment. If you have any questions about TRADJENTA, ask your doctor or pharmacist.What is the most important information should know about TRADJENTATRADJENTA can cause serious side effects, including:Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking TRADJENTA, tell your doctor if you have ever had:inflammation of your pancreas (pancreatitis)a history of alcoholismstones in your gallbladder (gallstones)high blood triglyceride levels Stop taking TRADJENTA and call your doctor right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.Heart failure. Heart failure means your heart does not pump blood well enough. Before you start taking TRADJENTA, tell your doctor if you have ever had heart failure or have problems with your kidneys. Contact your doctor right away if you have any of the following symptoms:increasing shortness of breath or trouble breathing, especially when you lie downswelling or fluid retention, especially in the feet, ankles or legsan unusually fast increase in weightunusual tiredness These may be symptoms of heart failure.What is TRADJENTATRADJENTA is prescription medicine used along with diet and exercise to lower blood sugar in adults with type diabetes.TRADJENTA is not for people with type diabetes.TRADJENTA is not for people with diabetic ketoacidosis (increased ketones in the blood or urine).If you have had pancreatitis in the past, it is not known if you have higher chance of getting pancreatitis while you take TRADJENTA.It is not known if TRADJENTA is safe and effective in children under 18 years of age.Who should not take TRADJENTADo not take TRADJENTA if you:are allergic to linagliptin or any of the ingredients in TRADJENTA. See the end of this Medication Guide for complete list of ingredients in TRADJENTA.Symptoms of serious allergic reaction to TRADJENTA may include:skin rash, itching, flaking or peelingraised red patches on your skin (hives)swelling of your face, lips, tongue and throat that may cause difficulty in breathing or swallowingdifficulty with swallowing or breathing If you have any of these symptoms, stop taking TRADJENTA and call your doctor right away or go to the nearest hospital emergency room.What should tell my doctor before taking TRADJENTABefore taking TRADJENTA, tell your doctor about all of your medical conditions, including if you:have or have had inflammation of your pancreas (pancreatitis).are pregnant or plan to become pregnant. It is not known if TRADJENTA will harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant.are breastfeeding or plan to breastfeed. It is not known if TRADJENTA passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take TRADJENTA.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.TRADJENTA may affect the way other medicines work, and other medicines may affect how TRADJENTA works. Especially tell your doctor if you take: insulin or other medicines that can lower your blood sugarrifampin (Rifadin, Rimactane, Rifater, Rifamate), an antibiotic that is used to treat tuberculosisKnow the medicines you take. Keep list of them to show your doctor and pharmacist when you get new medicine.How should take TRADJENTATake TRADJENTA exactly as your doctor tells you to take it.Take tablet time each day with or without food.If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of TRADJENTA at the same time.Your doctor may tell you to take TRADJENTA along with other diabetes medicines. Low blood sugar can happen more often when TRADJENTA is taken with certain other diabetes medicines. See What are the possible side effects of TRADJENTA If you take too much TRADJENTA, call your doctor or local poison control center or go to the nearest hospital emergency room right away.Check your blood sugar as your doctor tells you to.What are the possible side effects of TRADJENTATRADJENTA may cause serious side effects, including:See What is the most important information should know about TRADJENTA Low blood sugar (hypoglycemia). If you take TRADJENTA with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take TRADJENTA. Signs and symptoms of low blood sugar may include:headacheirritabilitydrowsinesshungerweaknessfast heartbeatdizzinesssweatingconfusionshaking or feeling jitteryAllergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking TRADJENTA. Symptoms may include:swelling of your face, lips, throat, and other areas on your skinraised, red areas on your skin (hives)difficulty with swallowing or breathingskin rash, itching, flaking, or peeling If you have any of these symptoms, stop taking TRADJENTA and call your doctor right away or go to the nearest hospital emergency room.Joint pain. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, may develop joint pain that can be severe. Call your doctor if you have severe joint pain.Skin reaction. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your doctor may tell you to stop taking TRADJENTA.The most common side effects of TRADJENTA include stuffy or runny nose and sore throat, cough, and diarrhea.Tell your doctor if you have any side effect that bothers you or that does not go away.These are not all the possible side effects of TRADJENTA. For more information, ask your doctor or pharmacist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TRADJENTAStore TRADJENTA at room temperature between 68F and 77F (20C and 25C).Keep TRADJENTA and all medicines out of the reach of children.General information about the safe and effective use of TRADJENTA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use TRADJENTA for condition for which it was not prescribed. Do not give TRADJENTA to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or doctor for information about TRADJENTA that is written for health professionals.What are the ingredients in TRADJENTAActive Ingredient: linagliptinInactive Ingredients: mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate. The film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol, and red ferric oxide.Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA. Licensed from: Boehringer Ingelheim International GmbH, Ingelheim, Germany.The other brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc. TRADJENTA is registered trademark of and used under license from Boehringer Ingelheim International GmbHBoehringer Ingelheim Pharmaceuticals, Inc. either owns or uses the CARMELINA(R) and CAROLINA(R) trademarks under license.Copyright (C) 2020 Boehringer Ingelheim International GmbH.ALL RIGHTS RESERVEDIT6174MC312020 For more information about TRADJENTA, including current prescribing information and Medication Guide, go to www.TRADJENTA.com, or scan the code below, or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906. Inflammation of the pancreas (pancreatitis) which may be severe and lead to death. Certain medical problems make you more likely to get pancreatitis. Before you start taking TRADJENTA, tell your doctor if you have ever had:. inflammation of your pancreas (pancreatitis). history of alcoholism. stones in your gallbladder (gallstones). high blood triglyceride levels. Stop taking TRADJENTA and call your doctor right away if you have pain in your stomach area (abdomen) that is severe and will not go away. The pain may be felt going from your abdomen to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.. Heart failure. Heart failure means your heart does not pump blood well enough. Before you start taking TRADJENTA, tell your doctor if you have ever had heart failure or have problems with your kidneys. Contact your doctor right away if you have any of the following symptoms:increasing shortness of breath or trouble breathing, especially when you lie downswelling or fluid retention, especially in the feet, ankles or legsan unusually fast increase in weightunusual tiredness These may be symptoms of heart failure.. increasing shortness of breath or trouble breathing, especially when you lie down. swelling or fluid retention, especially in the feet, ankles or legs. an unusually fast increase in weight. unusual tiredness. TRADJENTA is prescription medicine used along with diet and exercise to lower blood sugar in adults with type diabetes.. TRADJENTA is not for people with type diabetes.. TRADJENTA is not for people with diabetic ketoacidosis (increased ketones in the blood or urine).. If you have had pancreatitis in the past, it is not known if you have higher chance of getting pancreatitis while you take TRADJENTA.. It is not known if TRADJENTA is safe and effective in children under 18 years of age.. are allergic to linagliptin or any of the ingredients in TRADJENTA. See the end of this Medication Guide for complete list of ingredients in TRADJENTA.Symptoms of serious allergic reaction to TRADJENTA may include:skin rash, itching, flaking or peelingraised red patches on your skin (hives)swelling of your face, lips, tongue and throat that may cause difficulty in breathing or swallowingdifficulty with swallowing or breathing skin rash, itching, flaking or peeling. raised red patches on your skin (hives). swelling of your face, lips, tongue and throat that may cause difficulty in breathing or swallowing. difficulty with swallowing or breathing. have or have had inflammation of your pancreas (pancreatitis).. are pregnant or plan to become pregnant. It is not known if TRADJENTA will harm your unborn baby. If you are pregnant, talk with your doctor about the best way to control your blood sugar while you are pregnant.. are breastfeeding or plan to breastfeed. It is not known if TRADJENTA passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take TRADJENTA.. insulin or other medicines that can lower your blood sugar. rifampin (Rifadin, Rimactane, Rifater, Rifamate), an antibiotic that is used to treat tuberculosis. Take TRADJENTA exactly as your doctor tells you to take it.. Take tablet time each day with or without food.. If you miss dose, take it as soon as you remember. If you do not remember until it is time for your next dose, skip the missed dose and go back to your regular schedule. Do not take two doses of TRADJENTA at the same time.. Your doctor may tell you to take TRADJENTA along with other diabetes medicines. Low blood sugar can happen more often when TRADJENTA is taken with certain other diabetes medicines. See What are the possible side effects of TRADJENTA If you take too much TRADJENTA, call your doctor or local poison control center or go to the nearest hospital emergency room right away.. Check your blood sugar as your doctor tells you to.. See What is the most important information should know about TRADJENTA Low blood sugar (hypoglycemia). If you take TRADJENTA with another medicine that can cause low blood sugar, such as sulfonylurea or insulin, your risk of getting low blood sugar is higher. The dose of your sulfonylurea medicine or insulin may need to be lowered while you take TRADJENTA. Signs and symptoms of low blood sugar may include:. headache. irritability. drowsiness. hunger. weakness. fast heartbeat. dizziness. sweating. confusion. shaking or feeling jittery. Allergic (hypersensitivity) reactions. Serious allergic reactions have happened in people who are taking TRADJENTA. Symptoms may include:. swelling of your face, lips, throat, and other areas on your skin. raised, red areas on your skin (hives). difficulty with swallowing or breathing. skin rash, itching, flaking, or peeling. If you have any of these symptoms, stop taking TRADJENTA and call your doctor right away or go to the nearest hospital emergency room.. Joint pain. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, may develop joint pain that can be severe. Call your doctor if you have severe joint pain.. Skin reaction. Some people who take medicines called DPP-4 inhibitors like TRADJENTA, may develop skin reaction called bullous pemphigoid that can require treatment in hospital. Tell your doctor right away if you develop blisters or the breakdown of the outer layer of your skin (erosion). Your doctor may tell you to stop taking TRADJENTA.. Store TRADJENTA at room temperature between 68F and 77F (20C and 25C).. logo.

SPL UNCLASSIFIED SECTION.

Limitations of UseTRADJENTA should not be used in patients with type diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.TRADJENTA has not been studied in patients with history of pancreatitis. It is unknown whether patients with history of pancreatitis are at an increased risk for the development of pancreatitis while using TRADJENTA [see Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.

StorageStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThe limited data with TRADJENTA use in pregnant women are not sufficient to inform of drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed when linagliptin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure [see Data].The estimated background risk of major birth defects is to 10% in women with pre-gestational diabetes with HbA1c>7 and has been reported to be as high as 20 to 25% in women with HbA1c>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Animal DataNo adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively. These doses represent approximately 943 times (rats) and 1943 times (rabbits) the mg clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day to lactation day 21 at dose 49 times the mg clinical dose, based on exposure.. 8.2 Lactation. Risk SummaryThere is no information regarding the presence of linagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. However, linagliptin is present in rat milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TRADJENTA and any potential adverse effects on the breastfed child from TRADJENTA or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of TRADJENTA in pediatric patients under 18 years of age have not been established.. 8.5 Geriatric Use. In the 15 type diabetes studies with linagliptin, 1085 linagliptin-treated patients were 65 years of age and older (including 131 linagliptin-treated patients 75 years of age and older). Of these 15 studies, 12 were double-blind placebo-controlled. In these 12 studies, 591 linagliptin-treated patients were 65 years of age and older (including 82 linagliptin-treated patients 75 years of age and older). In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.. 8.6 Renal Impairment. No dose adjustment is recommended for patients with renal impairment [see Clinical Pharmacology (12.3)]. In the TRADJENTA treatment arm of the CARMELINA trial [see Clinical Studies (14.2)], 2200 (63%) patients had renal impairment (eGFR <60 mL/min/1.73 m2). Approximately 20% of the population had eGFR >=45 to <60 mL/min/1.73 m2, 28% of the population had eGFR >=30 to <45 mL/min/1.73 m2 and 15% had eGFR <30 mL/min/1.73 m2. The overall incidence of adverse reactions were generally similar between the TRADJENTA and placebo treatment arms.. 8.7 Hepatic Impairment. No dose adjustment is recommended for patients with hepatic impairment [see Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA. (5.1)Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of TRADJENTA in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (5.2)Hypoglycemia: When used with an insulin secretagogue (e.g., sulfonylurea (SU)) or insulin, consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia (5.3)Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with TRADJENTA. If hypersensitivity reactions occur, discontinue TRADJENTA, treat promptly, and monitor until signs and symptoms resolve. (5.4)Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.5)Bullous pemphigoid: There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue TRADJENTA. (5.6). Pancreatitis: There have been reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA. (5.1). Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of TRADJENTA in patients who have known risk factors for heart failure. Monitor for signs and symptoms. (5.2). Hypoglycemia: When used with an insulin secretagogue (e.g., sulfonylurea (SU)) or insulin, consider lowering the dose of the insulin secretagogue or insulin to reduce the risk of hypoglycemia (5.3). Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis, angioedema, and exfoliative skin conditions) have occurred with TRADJENTA. If hypersensitivity reactions occur, discontinue TRADJENTA, treat promptly, and monitor until signs and symptoms resolve. (5.4). Arthralgia: Severe and disabling arthralgia has been reported in patients taking DPP-4 inhibitors. Consider as possible cause for severe joint pain and discontinue drug if appropriate. (5.5). Bullous pemphigoid: There have been reports of bullous pemphigoid requiring hospitalization. Tell patients to report development of blisters or erosions. If bullous pemphigoid is suspected, discontinue TRADJENTA. (5.6). 5.1 Pancreatitis. Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with TRADJENTA. In the CARMELINA trial [see Clinical Studies (14.2)], acute pancreatitis was reported in (0.3%) patients treated with TRADJENTA and in (0.1%) patients treated with placebo. Two patients treated with TRADJENTA in the CARMELINA trial had acute pancreatitis with fatal outcome. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients treated with TRADJENTA.Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue TRADJENTA and initiate appropriate management. It is unknown whether patients with history of pancreatitis are at increased risk for the development of pancreatitis while using TRADJENTA.. 5.2 Heart Failure. An association between DPP-4 inhibitor treatment and heart failure has been observed in cardiovascular outcomes trials for two other members of the DPP-4 inhibitor class. These trials evaluated patients with type diabetes mellitus and atherosclerotic cardiovascular disease.Consider the risks and benefits of TRADJENTA prior to initiating treatment in patients at risk for heart failure, such as those with prior history of heart failure and history of renal impairment, and observe these patients for signs and symptoms of heart failure during therapy. Advise patients of the characteristic symptoms of heart failure and to immediately report such symptoms. If heart failure develops, evaluate and manage according to current standards of care and consider discontinuation of TRADJENTA.. 5.3 Use with Medications Known to Cause Hypoglycemia. Insulin secretagogues and insulin are known to cause hypoglycemia. The use of TRADJENTA in combination with an insulin secretagogue (e.g., sulfonylurea) or insulin was associated with higher rate of hypoglycemia compared with placebo in clinical trials [see Adverse Reactions (6.1)] The use of TRADJENTA in combination with insulin in subjects with severe renal impairment was associated with higher rate of hypoglycemia [see Adverse Reactions (6.1)]. Therefore, lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with TRADJENTA.. 5.4 Hypersensitivity Reactions. There have been postmarketing reports of serious hypersensitivity reactions in patients treated with TRADJENTA. These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred predominantly within the first months after initiation of treatment with TRADJENTA, with some reports occurring after the first dose. If serious hypersensitivity reaction is suspected, discontinue TRADJENTA, assess for other potential causes for the event, and institute alternative treatment for diabetes.Angioedema has also been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use caution in patient with history of angioedema to another DPP-4 inhibitor because it is unknown whether such patients will be predisposed to angioedema with TRADJENTA.. 5.5 Severe and Disabling Arthralgia. There have been postmarketing reports of severe and disabling arthralgia in patients taking DPP-4 inhibitors. The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication. subset of patients experienced recurrence of symptoms when restarting the same drug or different DPP-4 inhibitor. Consider DPP-4 inhibitors as possible cause for severe joint pain and discontinue drug if appropriate.. 5.6 Bullous Pemphigoid. Bullous pemphigoid was reported in (0.2%) patients treated with TRADJENTA compared to none in patients treated with placebo in the CARMELINA trial [see Clinical Studies (14.2)], and of these patients were hospitalized due to bullous pemphigoid. Postmarketing cases of bullous pemphigoid requiring hospitalization have been reported with DPP-4 inhibitor use. In reported cases, patients typically recovered with topical or systemic immunosuppressive treatment and discontinuation of the DPP-4 inhibitor. Tell patients to report development of blisters or erosions while receiving TRADJENTA. If bullous pemphigoid is suspected, TRADJENTA should be discontinued and referral to dermatologist should be considered for diagnosis and appropriate treatment.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. TRADJENTA tablets are available as light red, round, biconvex, bevel-edged, film-coated tablets containing mg of linagliptin. TRADJENTA tablets are debossed with D5 on one side and the Boehringer Ingelheim logo on the other side.They are supplied as follows:Bottles of 30 (NDC 0597-0140-30)Bottles of 90 (NDC 0597-0140-90)Cartons containing 10 blister cards of 10 tablets each (10 10) (NDC 0597-0140-61), institutional pack.If repackaging is required, dispense in tight container as defined in USP.. StorageStore at 20C to 25C (68F to 77F); excursions permitted to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature].

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following serious adverse reactions are described below or elsewhere in the prescribing information:Pancreatitis [see Warnings and Precautions (5.1)] Heart Failure [see Warnings and Precautions (5.2)] Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.3)] Hypersensitivity Reactions [see Warnings and Precautions (5.4)] Severe and Disabling Arthralgia [see Warnings and Precautions (5.5)] Bullous Pemphigoid [see Warnings and Precautions (5.6)] Pancreatitis [see Warnings and Precautions (5.1)] Heart Failure [see Warnings and Precautions (5.2)] Use with Medications Known to Cause Hypoglycemia [see Warnings and Precautions (5.3)] Hypersensitivity Reactions [see Warnings and Precautions (5.4)] Severe and Disabling Arthralgia [see Warnings and Precautions (5.5)] Bullous Pemphigoid [see Warnings and Precautions (5.6)] Adverse reactions reported in >=5% of patients treated with TRADJENTA and more commonly than in patients treated with placebo included nasopharyngitis (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257 or 1-800-459-9906 TTY, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety evaluation of TRADJENTA mg once daily in patients with type diabetes is based on 14 placebo-controlled trials, active-controlled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, total of 3625 patients were randomized and treated with TRADJENTA mg daily and 2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks.TRADJENTA mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks duration and in five additional placebo-controlled studies lasting <=18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks treatment duration); one with sulfonylurea (18 weeks treatment duration); one with metformin and sulfonylurea (24 weeks treatment duration); one with pioglitazone (24 weeks treatment duration); and one with insulin (primary endpoint at 24 weeks).In pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in >=2% of patients receiving TRADJENTA (n 3625) and more commonly than in patients given placebo (n 2176), are shown in Table 1. The overall incidence of adverse events with TRADJENTA were similar to placebo.Table Adverse Reactions Reported in >=2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination TherapyNumber (%) of PatientsTRADJENTA mgn 3625Placebon 2176Nasopharyngitis254 (7.0)132 (6.1)Diarrhea119 (3.3)65 (3.0)Cough76 (2.1)30 (1.4)Rates for other adverse reactions for TRADJENTA mg vs placebo when TRADJENTA was used in combination with specific anti-diabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.Following 104 weeks treatment in controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in >=5% of patients treated with TRADJENTA (n 776) and more frequently than in patients treated with sulfonylurea (n 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%).In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year 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.. HypoglycemiaTable summarizes the incidence of hypoglycemia in placebo-controlled studies of TRADJENTA. The incidence of hypoglycemia increased when TRADJENTA was administered with sulfonylurea or insulin.Table 2: Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRADJENTA in Patients with Type Diabetes MellitusHypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.Add-on to Sulfonylurea (18 Weeks)Placebo (N=84)TRADJENTA (N=161) Hypoglycemia with plasma glucose <54 mg/dL1.2%1.9% Severe hypoglycemia (%)0%0%Add-on to Metformin and Sulfonylurea (24 Weeks)Placebo (N=263)TRADJENTA (N=792) Hypoglycemia with plasma glucose <54 mg/dL5.3%8.1% Severe hypoglycemia (%)0.8%0.6%Add-on to Basal Insulin (52 Weeks)Placebo (N=630)TRADJENTA (N=631) Hypoglycemia with plasma glucose <54 mg/dL21.6%19.8% Severe hypoglycemia (%)1.1%1.7%In an active-controlled (glimepiride) cardiovascular safety study with TRADJENTA (CAROLINA) with median time on treatment of 5.9 years, the incidence of severe hypoglycemia was 0.3% in the TRADJENTA group (N=3014) and 2.2% in glimepiride group (N=3000).. Use in Renal ImpairmentTRADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed.In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials. The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose <=54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in (4.4%) TRADJENTA-treated patients and (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in (2.9%) patients on TRADJENTA and (1.5%) patient on placebo.Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks treatment compared to placebo.. Laboratory TestsChanges in laboratory findings were similar in patients treated with TRADJENTA mg compared to patients treated with placebo.. Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRADJENTA group and >=1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group). Increase in Lipase: In placebo-controlled clinical trial with TRADJENTA in type diabetes mellitus patients with micro- or macroalbuminuria, mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the TRADJENTA arm compared to mean decrease of 2% in the placebo arm. Lipase levels above times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively.. Increase in Amylase: In cardiovascular safety study comparing TRADJENTA versus glimepiride in patients with type diabetes mellitus, amylase levels above times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively.The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.1)]. Vital SignsNo clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.. 6.2 Postmarketing Experience. Additional adverse reactions have been identified during postapproval use of TRADJENTA. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1)] Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditionsSevere and disabling arthralgiaBullous pemphigoidRashMouth ulceration, stomatitisRhabdomyolysis. Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1)] Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions. Severe and disabling arthralgia. Bullous pemphigoid. Rash. Mouth ulceration, stomatitis. Rhabdomyolysis.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Linagliptin did not increase the incidence of tumors in male and female rats in 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 mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in 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, 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in reduction in hepatic glucose output.. 12.2 Pharmacodynamics. Linagliptin binds to DPP-4 in reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.. Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered single oral dose of linagliptin mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following 5-mg dose.. 12.3 Pharmacokinetics. The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type diabetes. After oral administration of single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmolh/L and maximum concentration (Cmax) was 8.9 nmol/L.Plasma concentrations of linagliptin decline in at least biphasic manner with long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin mg are reached by the third dose, and Cmax and AUC increased by factor of 1.3 at steady-state compared with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in less than dose-proportional manner in the dose range of to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type diabetes.. AbsorptionThe absolute bioavailability of linagliptin is approximately 30%. high-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered with or without food.. DistributionThe mean apparent volume of distribution at steady-state following single intravenous dose of linagliptin mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at nmol/L to 75%-89% at >=30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.. EliminationLinagliptin has terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.. MetabolismFollowing oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents minor elimination pathway. small fraction of absorbed linagliptin is metabolized to pharmacologically inactive metabolite, which shows steady-state exposure of 13.3% relative to linagliptin.. ExcretionFollowing administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within days of dosing.. Specific Populations. Renal ImpairmentAn open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin mg in male and female patients with varying degrees of chronic renal impairment. The study included healthy subjects with normal renal function (creatinine clearance [CrCl] >=80 mL/min), patients with mild renal impairment (CrCl 50 to <80 mL/min), patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type diabetes mellitus and severe renal impairment (CrCl <30 mL/min), and 11 patients with type diabetes mellitus and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUC,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function.Patients with type diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type diabetes mellitus and normal renal function (increase in AUC,ss by 42% and Cmax by 35%). For both type diabetes mellitus groups, renal excretion was below 7% of the administered dose.These findings were further supported by the results of population pharmacokinetic analyses.. Hepatic ImpairmentIn patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUC,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.. Body Mass Index (BMI)/WeightNo dose adjustment is necessary based on BMI/weight. BMI/weight had no clinically meaningful effect on the pharmacokinetics of linagliptin based on population pharmacokinetic analysis.. GenderNo dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on population pharmacokinetic analysis.. GeriatricAge did not have clinically meaningful impact on the pharmacokinetics of linagliptin based on population pharmacokinetic analysis.. PediatricStudies characterizing the pharmacokinetics of linagliptin in pediatric patients have not yet been performed.. RaceNo dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on available pharmacokinetic data, including subjects of White, Hispanic, Black, and Asian racial groups.. Drug Interactions. In vitro Assessment of Drug InteractionsLinagliptin is weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.Linagliptin is P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.. In vivo Assessment of Drug InteractionsStrong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations [see Drug Interactions (7)]. In vivo studies indicated evidence of low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).Table Effect of Coadministered Drugs on Systemic Exposure of Linagliptin Coadministered Drug Dosing of Coadministered Drug Dosing of Linagliptin Geometric Mean Ratio(ratio with/without coadministered drug)No effect 1.0 AUC+ Cmax Multiple dose (steady-state) unless otherwise notedFor information regarding clinical recommendations [see Drug Interactions (7.1)]. Single dose +AUC AUC(0 to 24 hours) for single-dose treatments and AUC AUC(TAU) for multiple-dose treatmentsQD once dailyBID twice dailyTID three times dailyMetformin850 mg TID10 mg QD1.201.03Glyburide1.75 mg mg QD1.021.01Pioglitazone45 mg QD10 mg QD1.131.07Ritonavir200 mg BID5 mg 2.012.96Rifampin600 mg QD5 mg QD0.600.56Table Effect of Linagliptin on Systemic Exposure of Coadministered DrugsCoadministered Drug Dosing of Coadministered Drug Dosing of Linagliptin Geometric Mean Ratio(ratio with/without coadministered drug)No effect 1.0 AUC+ Cmax Multiple dose (steady-state) unless otherwise notedSingle dose +AUC=AUC(INF) for single-dose treatments and AUC AUC(TAU) for multiple-dose treatmentsAUC=AUC(0-168) and Cmax=Emax for pharmacodynamic end points INR International Normalized RatioPT Prothrombin TimeQD once dailyTID three times dailyMetformin850 mg TID10 mg QDmetformin1.010.89Glyburide1.75 mg mg QDglyburide0.860.86Pioglitazone45 mg QD10 mg QDpioglitazonemetabolite M-IIImetabolite M-IV0.940.981.040.860.961.05Digoxin0.25 mg QD5 mg QDdigoxin1.020.94Simvastatin40 mg QD10 mg QDsimvastatinsimvastatin acid1.341.331.101.21Warfarin10 mg mg QDR-warfarinS-warfarinINRPT0.991.030.93 1.03 1.001.011.04 1.15 Ethinylestradiol and levonorgestrelethinylestradiol 0.03 mg andlevonorgestrel 0.150 mg QD5 mg QDethinylestradiollevonorgestrel1.011.091.081.13.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. TRADJENTA is contraindicated in patients with hypersensitivity to linagliptin or any of the excipients in TRADJENTA, reactions such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity have occurred [see Warnings and Precautions (5.4) and Adverse Reactions (6)]. Hypersensitivity to linagliptin or any of the excipients in TRADJENTA. (4, 5.4).

DESCRIPTION SECTION.

11 DESCRIPTION. TRADJENTA (linagliptin) tablets contain, as the active ingredient, an orally-active inhibitor of the dipeptidyl peptidase-4 (DPP-4) enzyme.Linagliptin is described chemically as 1H-Purine-2,6-dione, 8-[(3R)-3-amino-1-piperidinyl]-7-(2-butyn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methyl-2-quinazolinyl)methyl]-The empirical formula is C25H28N8O2 and the molecular weight is 472.54 g/mol. The structural formula is:Linagliptin is white to yellowish, not or only slightly hygroscopic solid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly soluble in ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1 mg/mL), and very slightly soluble in acetone (ca. mg/mL).Each film-coated tablet of TRADJENTA contains mg of linagliptin free base and the following inactive ingredients: mannitol, pregelatinized starch, corn starch, copovidone, and magnesium stearate. In addition, the film coating contains the following inactive ingredients: hypromellose, titanium dioxide, talc, polyethylene glycol, and red ferric oxide.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dose of TRADJENTA is mg once daily (2.1)TRADJENTA can be taken with or without food (2.1). The recommended dose of TRADJENTA is mg once daily (2.1). TRADJENTA can be taken with or without food (2.1). 2.1 Recommended Dosing. The recommended dose of TRADJENTA is mg once daily.TRADJENTA tablets can be taken with or without food.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. TRADJENTA (linagliptin) mg tablets are light red, round, biconvex, bevel-edged, film-coated tablets with D5 debossed on one side and the Boehringer Ingelheim logo debossed on the other side.. Tablets: mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Strong P-glycoprotein/CYP3A4 inducer: The efficacy of TRADJENTA may be reduced when administered in combination (e.g., with rifampin). Use of alternative treatments is strongly recommended. (7.1). 7.1 Inducers of P-glycoprotein or CYP3A4 Enzymes. Rifampin decreased linagliptin exposure, suggesting that the efficacy of TRADJENTA may be reduced when administered in combination with strong P-gp or CYP3A4 inducer. Therefore, use of alternative treatments is strongly recommended when linagliptin is to be administered with strong P-gp or CYP3A4 inducer [see Clinical Pharmacology (12.3)].. 7.2 Insulin Secretagogues or Insulin. Coadministration of TRADJENTA with an insulin secretagogue (e.g., sulfonylurea) or insulin may require lower doses of the insulin secretagogue or insulin to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. In the 15 type diabetes studies with linagliptin, 1085 linagliptin-treated patients were 65 years of age and older (including 131 linagliptin-treated patients 75 years of age and older). Of these 15 studies, 12 were double-blind placebo-controlled. In these 12 studies, 591 linagliptin-treated patients were 65 years of age and older (including 82 linagliptin-treated patients 75 years of age and older). In these linagliptin studies, no overall differences in safety or effectiveness of linagliptin were observed between geriatric patients and younger adult patients.

HEPATIC IMPAIRMENT SUBSECTION.

8.7 Hepatic Impairment. No dose adjustment is recommended for patients with hepatic impairment [see Clinical Pharmacology (12.3)].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. TRADJENTA is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus [see Clinical Studies (14.1)]. TRADJENTA is dipeptidyl peptidase-4 (DPP-4) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus (1)Limitations of UseShould not be used in patients with type diabetes or for the treatment of diabetic ketoacidosis (1)Has not been studied in patients with history of pancreatitis (1). Should not be used in patients with type diabetes or for the treatment of diabetic ketoacidosis (1). Has not been studied in patients with history of pancreatitis (1). Limitations of UseTRADJENTA should not be used in patients with type diabetes or for the treatment of diabetic ketoacidosis, as it would not be effective in these settings.TRADJENTA has not been studied in patients with history of pancreatitis. It is unknown whether patients with history of pancreatitis are at an increased risk for the development of pancreatitis while using TRADJENTA [see Warnings and Precautions (5.1)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide).. PancreatitisInform patients that acute pancreatitis has been reported during use of TRADJENTA. Inform patients that persistent severe abdominal pain, sometimes radiating to the back, which may or may not be accompanied by vomiting, is the hallmark symptom of acute pancreatitis. Instruct patients to discontinue TRADJENTA promptly and contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.1)].. Heart FailureInform patients of the signs and symptoms of heart failure. Before initiating TRADJENTA, patients should be asked about history of heart failure or other risk factors for heart failure including moderate to severe renal impairment. Instruct patients to contact their healthcare provider as soon as possible if they experience symptoms of heart failure, including increasing shortness of breath, rapid increase in weight or swelling of the feet [see Warnings and Precautions (5.2)]. HypoglycemiaInform patients that the incidence of hypoglycemia is increased when TRADJENTA is added to sulfonylurea or insulin and that lower dose of the sulfonylurea or insulin may be required to reduce the risk of hypoglycemia [see Warnings and Precautions (5.3)].. Hypersensitivity ReactionsInform patients that serious allergic reactions, such as anaphylaxis, angioedema, and exfoliative skin conditions, have been reported during postmarketing use of TRADJENTA. If symptoms of allergic reactions (such as rash, skin flaking or peeling, urticaria, swelling of the skin, or swelling of the face, lips, tongue, and throat that may cause difficulty in breathing or swallowing) occur, patients must stop taking TRADJENTA and seek medical advice promptly [see Warnings and Precautions (5.4)].. Severe and Disabling ArthralgiaInform patients that severe and disabling joint pain may occur with this class of drugs. The time to onset of symptoms can range from one day to years. Instruct patients to seek medical advice if severe joint pain occurs [see Warnings and Precautions (5.5)]. Bullous PemphigoidInform patients that bullous pemphigoid has been reported during use of TRADJENTA. Instruct patients to seek medical advice if blisters or erosions occur [see Warnings and Precautions (5.6)]. Missed DoseInstruct patients to take TRADJENTA only as prescribed. If dose is missed, advise patients not to double their next dose.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere is no information regarding the presence of linagliptin in human milk, the effects on the breastfed infant, or the effects on milk production. However, linagliptin is present in rat milk. Therefore, the developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for TRADJENTA and any potential adverse effects on the breastfed child from TRADJENTA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Linagliptin is an inhibitor of DPP-4, an enzyme that degrades the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Thus, linagliptin increases the concentrations of active incretin hormones, stimulating the release of insulin in glucose-dependent manner and decreasing the levels of glucagon in the circulation. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin hormones are secreted at low basal level throughout the day and levels rise immediately after meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presence of normal and elevated blood glucose levels. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha-cells, resulting in reduction in hepatic glucose output.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Linagliptin did not increase the incidence of tumors in male and female rats in 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 mg/day based on AUC exposure. Linagliptin did not increase the incidence of tumors in mice in 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, 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).

OVERDOSAGE SECTION.

10 OVERDOSAGE. In the event of an overdose with TRADJENTA, contact the Poison Control Center. Removal of linagliptin by hemodialysis or peritoneal dialysis is unlikely.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 5 mg Tablet Blister Card Carton. NDC 0597-0140-61DISPENSE THE ACCOMPANYINGMEDICATION GUIDE TO EACH PATIENTTradjenta(R) (linagliptin tablets)5 mg per tabletDosage: Take one tablet daily. See package insert for full dosage information.100 tablets 10 blister cards of 10 tabletsThis unit dose package is not child-resistant. If dispensed for outpatient use, child-resistant container should be utilized.Rx onlyBoehringer Ingelheim. PRINCIPAL DISPLAY PANEL 5 mg Tablet Blister Card Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of TRADJENTA in pediatric patients under 18 years of age have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Linagliptin binds to DPP-4 in reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.. Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered single oral dose of linagliptin mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38-fold higher than the peak concentrations following 5-mg dose.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type diabetes. After oral administration of single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmolh/L and maximum concentration (Cmax) was 8.9 nmol/L.Plasma concentrations of linagliptin decline in at least biphasic manner with long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin mg are reached by the third dose, and Cmax and AUC increased by factor of 1.3 at steady-state compared with the first dose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in less than dose-proportional manner in the dose range of to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type diabetes.. AbsorptionThe absolute bioavailability of linagliptin is approximately 30%. high-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRADJENTA may be administered with or without food.. DistributionThe mean apparent volume of distribution at steady-state following single intravenous dose of linagliptin mg to healthy subjects is approximately 1110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at nmol/L to 75%-89% at >=30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.. EliminationLinagliptin has terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.. MetabolismFollowing oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents minor elimination pathway. small fraction of absorbed linagliptin is metabolized to pharmacologically inactive metabolite, which shows steady-state exposure of 13.3% relative to linagliptin.. ExcretionFollowing administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within days of dosing.. Specific Populations. Renal ImpairmentAn open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin mg in male and female patients with varying degrees of chronic renal impairment. The study included healthy subjects with normal renal function (creatinine clearance [CrCl] >=80 mL/min), patients with mild renal impairment (CrCl 50 to <80 mL/min), patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type diabetes mellitus and severe renal impairment (CrCl <30 mL/min), and 11 patients with type diabetes mellitus and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUC,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function.Patients with type diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type diabetes mellitus and normal renal function (increase in AUC,ss by 42% and Cmax by 35%). For both type diabetes mellitus groups, renal excretion was below 7% of the administered dose.These findings were further supported by the results of population pharmacokinetic analyses.. Hepatic ImpairmentIn patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUC,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.. Body Mass Index (BMI)/WeightNo dose adjustment is necessary based on BMI/weight. BMI/weight had no clinically meaningful effect on the pharmacokinetics of linagliptin based on population pharmacokinetic analysis.. GenderNo dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on population pharmacokinetic analysis.. GeriatricAge did not have clinically meaningful impact on the pharmacokinetics of linagliptin based on population pharmacokinetic analysis.. PediatricStudies characterizing the pharmacokinetics of linagliptin in pediatric patients have not yet been performed.. RaceNo dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on available pharmacokinetic data, including subjects of White, Hispanic, Black, and Asian racial groups.. Drug Interactions. In vitro Assessment of Drug InteractionsLinagliptin is weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.Linagliptin is P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.. In vivo Assessment of Drug InteractionsStrong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations [see Drug Interactions (7)]. In vivo studies indicated evidence of low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).Table Effect of Coadministered Drugs on Systemic Exposure of Linagliptin Coadministered Drug Dosing of Coadministered Drug Dosing of Linagliptin Geometric Mean Ratio(ratio with/without coadministered drug)No effect 1.0 AUC+ Cmax Multiple dose (steady-state) unless otherwise notedFor information regarding clinical recommendations [see Drug Interactions (7.1)]. Single dose +AUC AUC(0 to 24 hours) for single-dose treatments and AUC AUC(TAU) for multiple-dose treatmentsQD once dailyBID twice dailyTID three times dailyMetformin850 mg TID10 mg QD1.201.03Glyburide1.75 mg mg QD1.021.01Pioglitazone45 mg QD10 mg QD1.131.07Ritonavir200 mg BID5 mg 2.012.96Rifampin600 mg QD5 mg QD0.600.56Table Effect of Linagliptin on Systemic Exposure of Coadministered DrugsCoadministered Drug Dosing of Coadministered Drug Dosing of Linagliptin Geometric Mean Ratio(ratio with/without coadministered drug)No effect 1.0 AUC+ Cmax Multiple dose (steady-state) unless otherwise notedSingle dose +AUC=AUC(INF) for single-dose treatments and AUC AUC(TAU) for multiple-dose treatmentsAUC=AUC(0-168) and Cmax=Emax for pharmacodynamic end points INR International Normalized RatioPT Prothrombin TimeQD once dailyTID three times dailyMetformin850 mg TID10 mg QDmetformin1.010.89Glyburide1.75 mg mg QDglyburide0.860.86Pioglitazone45 mg QD10 mg QDpioglitazonemetabolite M-IIImetabolite M-IV0.940.981.040.860.961.05Digoxin0.25 mg QD5 mg QDdigoxin1.020.94Simvastatin40 mg QD10 mg QDsimvastatinsimvastatin acid1.341.331.101.21Warfarin10 mg mg QDR-warfarinS-warfarinINRPT0.991.030.93 1.03 1.001.011.04 1.15 Ethinylestradiol and levonorgestrelethinylestradiol 0.03 mg andlevonorgestrel 0.150 mg QD5 mg QDethinylestradiollevonorgestrel1.011.091.081.13.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions Pancreatitis (5.1)7/2019 Bullous Pemphigoid (5.6)7/2019 Macrovascular Outcomes- Removed7/2019.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety evaluation of TRADJENTA mg once daily in patients with type diabetes is based on 14 placebo-controlled trials, active-controlled study, and one study in patients with severe renal impairment. In the 14 placebo-controlled studies, total of 3625 patients were randomized and treated with TRADJENTA mg daily and 2176 with placebo. The mean exposure in patients treated with TRADJENTA across studies was 29.6 weeks. The maximum follow-up was 78 weeks.TRADJENTA mg once daily was studied as monotherapy in three placebo-controlled trials of 18 and 24 weeks duration and in five additional placebo-controlled studies lasting <=18 weeks. The use of TRADJENTA in combination with other antihyperglycemic agents was studied in six placebo-controlled trials: two with metformin (12 and 24 weeks treatment duration); one with sulfonylurea (18 weeks treatment duration); one with metformin and sulfonylurea (24 weeks treatment duration); one with pioglitazone (24 weeks treatment duration); and one with insulin (primary endpoint at 24 weeks).In pooled dataset of 14 placebo-controlled clinical trials, adverse reactions that occurred in >=2% of patients receiving TRADJENTA (n 3625) and more commonly than in patients given placebo (n 2176), are shown in Table 1.Table Adverse Reactions Reported in >=2% of Patients Treated with TRADJENTA and Greater than Placebo in Placebo-Controlled Clinical Studies of TRADJENTA Monotherapy or Combination TherapyAdverse ReactionsTRADJENTA mg (%)n 3625Placebo (%)n 2176Nasopharyngitis7.06.1Diarrhea3.33.0Cough2.11.4Rates for other adverse reactions for TRADJENTA mg vs placebo when TRADJENTA was used in combination with specific antidiabetic agents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when TRADJENTA was used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%) and weight increased (2.3% vs 0.8%) when TRADJENTA was used as add-on to pioglitazone; and constipation (2.1% vs 1%) when TRADJENTA was used as add-on to basal insulin therapy. Other adverse reactions reported in clinical studies with treatment of TRADJENTA were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.Following 104 weeks treatment in controlled study comparing TRADJENTA with glimepiride in which all patients were also receiving metformin, adverse reactions reported in >=5% of patients treated with TRADJENTA (n 776) and more frequently than in patients treated with sulfonylurea (n 775) were back pain (9.1% vs 8.4%), arthralgia (8.1% vs 6.1%), upper respiratory tract infection (8.0% vs 7.6%), headache (6.4% vs 5.2%), cough (6.1% vs 4.9%), and pain in extremity (5.3% vs 3.9%).In the clinical trial program, pancreatitis was reported in 15.2 cases per 10,000 patient year exposure while being treated with TRADJENTA compared with 3.7 cases per 10,000 patient year 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.. HypoglycemiaTable summarizes the incidence of hypoglycemia in placebo-controlled studies of TRADJENTA. The incidence of hypoglycemia increased when TRADJENTA was administered with sulfonylurea or insulin.Table Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of TRADJENTA in Patients with Type Diabetes MellitusHypoglycemia requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.Add-on to Sulfonylurea (18 Weeks)Placebo (N=84)TRADJENTA (N=161) Hypoglycemia with plasma glucose <54 mg/dL (%)1.21.9 Severe hypoglycemia (%)00Add-on to Metformin and Sulfonylurea (24 Weeks)Placebo (N=263)TRADJENTA (N=792) Hypoglycemia with plasma glucose <54 mg/dL (%)5.38.1 Severe hypoglycemia (%)0.80.6Add-on to Basal Insulin (52 Weeks)Placebo (N=630)TRADJENTA (N=631) Hypoglycemia with plasma glucose <54 mg/dL (%)21.619.8 Severe hypoglycemia (%)1.11.7In an active-controlled (glimepiride) cardiovascular safety study with TRADJENTA (CAROLINA) with median time on treatment of 5.9 years, the incidence of severe hypoglycemia was 0.3% in the TRADJENTA group (N=3014) and 2.2% in glimepiride group (N=3000).. Use in Renal ImpairmentTRADJENTA was compared to placebo as add-on to pre-existing antidiabetic therapy over 52 weeks in 133 patients with severe renal impairment (estimated GFR <30 mL/min). For the initial 12 weeks of the study, background antidiabetic therapy was kept stable and included insulin, sulfonylurea, glinides, and pioglitazone. For the remainder of the trial, dose adjustments in antidiabetic background therapy were allowed.In general, the incidence of adverse events including severe hypoglycemia was similar to those reported in other TRADJENTA trials. The observed incidence of hypoglycemia was higher (TRADJENTA, 63% compared to placebo, 49%) due to an increase in asymptomatic hypoglycemic events especially during the first 12 weeks when background glycemic therapies were kept stable. Ten TRADJENTA-treated patients (15%) and 11 placebo-treated patients (17%) reported at least one episode of confirmed symptomatic hypoglycemia (accompanying finger stick glucose <=54 mg/dL). During the same time period, severe hypoglycemic events, defined as an event requiring the assistance of another person to actively administer carbohydrate, glucagon or other resuscitative actions, were reported in (4.4%) TRADJENTA-treated patients and (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in (2.9%) patients on TRADJENTA and (1.5%) patient on placebo.Renal function as measured by mean eGFR and creatinine clearance did not change over 52 weeks treatment compared to placebo.. Laboratory TestsChanges in laboratory findings were similar in patients treated with TRADJENTA mg compared to patients treated with placebo.. Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRADJENTA group and >=1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group).. Increase in Lipase: In placebo-controlled clinical trial with TRADJENTA in type diabetes mellitus patients with micro- or macroalbuminuria, mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the TRADJENTA arm compared to mean decrease of 2% in the placebo arm. Lipase levels above times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively.. Increase in Amylase: In cardiovascular safety study comparing TRADJENTA versus glimepiride in patients with type diabetes mellitus, amylase levels above times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively.The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.1)]. Vital SignsNo clinically meaningful changes in vital signs were observed in patients treated with TRADJENTA.

LABORATORY TESTS SECTION.

Laboratory TestsChanges in laboratory findings were similar in patients treated with TRADJENTA mg compared to patients treated with placebo.. Increase in Uric Acid: Changes in laboratory values that occurred more frequently in the TRADJENTA group and >=1% more than in the placebo group were increases in uric acid (1.3% in the placebo group, 2.7% in the TRADJENTA group).. Increase in Lipase: In placebo-controlled clinical trial with TRADJENTA in type diabetes mellitus patients with micro- or macroalbuminuria, mean increase of 30% in lipase concentrations from baseline to 24 weeks was observed in the TRADJENTA arm compared to mean decrease of 2% in the placebo arm. Lipase levels above times upper limit of normal were seen in 8.2% compared to 1.7% patients in the TRADJENTA and placebo arms, respectively.. Increase in Amylase: In cardiovascular safety study comparing TRADJENTA versus glimepiride in patients with type diabetes mellitus, amylase levels above times upper limit of normal were seen in 1.0% compared to 0.5% of patients in the TRADJENTA and glimepiride arms, respectively.The clinical significance of elevations in lipase and amylase with TRADJENTA is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.1)].

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. Additional adverse reactions have been identified during postapproval use of TRADJENTA. Because these reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure.Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1)] Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditionsSevere and disabling arthralgiaBullous pemphigoidRashMouth ulceration, stomatitisRhabdomyolysis. Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1)] Hypersensitivity reactions including anaphylaxis, angioedema, and exfoliative skin conditions. Severe and disabling arthralgia. Bullous pemphigoid. Rash. Mouth ulceration, stomatitis. Rhabdomyolysis.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThe limited data with TRADJENTA use in pregnant women are not sufficient to inform of drug-associated risk for major birth defects and miscarriage. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations]. In animal reproduction studies, no adverse developmental effects were observed when linagliptin was administered to pregnant rats during the period of organogenesis at doses similar to the maximum recommended clinical dose, based on exposure [see Data].The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo/fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.. Data. Animal DataNo adverse developmental outcome was observed when linagliptin was administered to pregnant Wistar Han rats and Himalayan rabbits during the period of organogenesis at doses up to 240 mg/kg/day and 150 mg/kg/day, respectively. These doses represent approximately 943-times (rats) and 1943-times (rabbits) the mg maximum clinical dose, based on exposure. No adverse functional, behavioral, or reproductive outcome was observed in offspring following administration of linagliptin to Wistar Han rats from gestation day to lactation day 21 at dose 49-times the maximum recommended human dose, based on exposure.Linagliptin crosses the placenta into the fetus following oral dosing in pregnant rats and rabbits.