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 withlinagliptin and more commonly than in patients treated with placeboincluded nasopharyngitis (6.1) To report SUSPECTED ADVERSE REACTIONS, contact HEC Pharm USA Inc. at 1-267-348-3664 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical TrialsExperience. Because clinicaltrials are conducted under widely varying conditions, adverse reactionrates observed in the clinical trials of drug cannot be directlycompared to rates in the clinical trials of another drug and may notreflect the rates observed in practice.The safety evaluation of linagliptin mg once daily inpatients 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 3625patients were randomized and treated with linagliptin mg daily and2176 with placebo. The mean exposure in patients treated with linagliptinacross studies was 29.6 weeks. The maximum follow-up was 78 weeks.Linagliptin mg once daily was studied asmonotherapy in three placebo-controlled trials of 18 and 24 weeksduration and in five additional placebo-controlled studies lasting<=18 weeks. The use of linagliptin in combination with other antihyperglycemicagents was studied in six placebo-controlled trials: two with metformin(12 and 24 weeks treatment duration); one with sulfonylurea (18weeks treatment duration); one with metformin and sulfonylurea (24weeks treatment duration); one with pioglitazone (24 weeks treatmentduration); and one with insulin (primary endpoint at 24 weeks).In pooled dataset of 14 placebo-controlledclinical trials, adverse reactions that occurred in >=2% of patientsreceiving linagliptin (n 3625) and more commonly than in patientsgiven placebo (n 2176), are shown in Table 1. The overall incidenceof adverse events with linagliptin were similar to placebo.Table Adverse Reactions Reported in >=2% of Patients Treatedwith Linagliptin and Greater than Placebo in Placebo-Controlled ClinicalStudies of Linagliptin Monotherapy or Combination Therapy Number (%) of PatientsLinagliptin5 mg = 3625 Placebo = 2176 Nasopharyngitis254 (7.0)132 (6.1)Diarrhea119 (3.3)65 (3.0)Cough76 (2.1)30 (1.4)Rates for other adverse reactionsfor linagliptin mg vs placebo when linagliptin was used in combinationwith specific anti-diabetic agents were: urinary tract infection(3.1% vs 0%) and hypertriglyceridemia (2.4% vs 0%) when linagliptinwas used as add-on to sulfonylurea; hyperlipidemia (2.7% vs 0.8%)and weight increased (2.3% vs 0.8%) when linagliptin was used as add-onto pioglitazone; and constipation (2.1% vs 1%) when linagliptin wasused as add-on to basal insulin therapy. Other adverse reactions reported in clinical studies with treatment of linagliptin were hypersensitivity (e.g., urticaria, angioedema, localized skin exfoliation, or bronchial hyperreactivity) and myalgia.Following 104 weeks treatment in controlled studycomparing linagliptin with glimepiride in which all patients were alsoreceiving metformin, adverse reactions reported in >=5% of patientstreated with linagliptin (n 776) and more frequently than in patientstreated 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 painin extremity (5.3% vs 3.9%).In the clinicaltrial program, pancreatitis was reported in 15.2 cases per 10,000patient year exposure while being treated with linagliptin comparedwith 3.7 cases per 10,000 patient year exposure while being treatedwith comparator (placebo and active comparator, sulfonylurea). Threeadditional cases of pancreatitis were reported following the lastadministered dose of linagliptin.. HypoglycemiaTable summarizes the incidence of hypoglycemia in placebo-controlled studies of linagliptin. The incidence of hypoglycemia increased when linagliptin was administered with sulfonylurea or insulin.Table 2: Incidence (%) of Hypoglycemia in Placebo-Controlled Clinical Studies of Linagliptin 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)Linagliptin (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)Linagliptin (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)Linagliptin (N=631) Hypoglycemia with plasma glucose <54 mg/dL21.6%19.8% Severe hypoglycemia (%)1.1%1.7%. Use in Renal ImpairmentLinagliptin 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 linagliptin trials. The observed incidence of hypoglycemia was higher (linagliptin, 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 linagliptin-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%) linagliptin-treated patients and (4.6%) placebo-treated patients. Events that were considered life-threatening or required hospitalization were reported in (2.9%) patients on linagliptin 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 Tests. Changes in laboratoryfindings were similar in patients treated with linagliptin mg comparedto patients treated with placebo. Increase in Uric Acid: Changes in laboratory values thatoccurred more frequently in the linagliptin group and >1% more than in the placebo group were increases in uric acid (1.3%in the placebo group, 2.7% in the linagliptin group). Increase in Lipase: In placebo-controlled clinical trial with linagliptin in type 2diabetes mellitus patients with micro- or macroalbuminuria, meanincrease of 30% in lipase concentrations from baseline to 24 weekswas observed in the linagliptin arm compared to mean decrease of 2%in the placebo arm. Lipase levels above times upper limit of normalwere seen in 8.2% compared to 1.7% patients in the linagliptin and placeboarms, respectively. The clinical significance of elevations in lipase with linagliptin is unknown in the absence of potential signs and symptoms of pancreatitis [see Warnings and Precautions (5.1)]. VitalSignsNo clinically meaningful changes in vital signs wereobserved in patients treated with linagliptin. 6.2 Postmarketing Experience. Additional adverse reactions have been identified duringpostapproval use of linagliptin. Because these reactions are reportedvoluntarily from population of uncertain size, it is generally notpossible to reliably estimate their frequency or establish causalrelationship 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Linagliptin is an inhibitor of DPP-4, an enzyme that degrades theincretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependentinsulinotropic polypeptide (GIP). Thus, linagliptin increases theconcentrations of active incretin hormones, stimulating the releaseof insulin in glucose-dependent manner and decreasing the levelsof glucagon in the circulation. Both incretin hormones are involvedin the physiological regulation of glucose homeostasis. Incretin hormonesare secreted at low basal level throughout the day and levels riseimmediately after meal intake. GLP-1 and GIP increase insulin biosynthesisand secretion from pancreatic beta cells in the presence of normaland elevated blood glucose levels. Furthermore, GLP-1 also reducesglucagon secretion from pancreatic alpha-cells, resulting in reductionin hepatic glucose output. 12.2 Pharmacodynamics. Linagliptin binds to DPP-4 in reversible manner and thus increasesthe concentrations of incretin hormones. Linagliptin glucose dependentlyincreases insulin secretion and lowers glucagon secretion, thus resultingin better regulation of glucose homeostasis. Linagliptin binds selectivelyto DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximatingtherapeutic exposures. Cardiac Electrophysiology. In randomized, placebo-controlled,active-comparator, 4-way crossover study, 36 healthy subjects wereadministered single oral dose of linagliptin mg, linagliptin 100mg (20 times the recommended dose), moxifloxacin, and placebo. Noincrease in QTc was observed with either the recommended dose of 5mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasmaconcentrations were approximately 38-fold higher than the peak concentrationsfollowing 5-mg dose.. 12.3 Pharmacokinetics. The pharmacokinetics of linagliptin has been characterized in healthysubjects and patients with type diabetes. After oral administrationof single 5-mg dose to healthy subjects, peak plasma concentrationsof linagliptin occurred at approximately 1.5 hours post dose (T max); the mean plasma area under the curve (AUC) was139 nmolh/L and maximum concentration (C max) was 8.9 nmol/L. Plasma concentrationsof linagliptin decline in at least biphasic manner with long terminalhalf-life (>100 hours), related to the saturable binding of linagliptinto DPP-4. The prolonged elimination phase does not contribute to theaccumulation of the drug. The effective half-life for accumulationof linagliptin, as determined from oral administration of multipledoses of linagliptin mg, is approximately 12 hours. After once-dailydosing, steady-state plasma concentrations of linagliptin mg arereached by the third dose, and max and AUCincreased by factor of 1.3 at steady-state compared with the firstdose. The intra-subject and inter-subject coefficients of variationfor linagliptin AUC were small (12.6% and 28.5%, respectively). PlasmaAUC of linagliptin increased in less than dose-proportional mannerin the dose range of to 10 mg. The pharmacokinetics of linagliptinis similar in healthy subjects and in patients with type diabetes. Absorption. The absolute bioavailabilityof linagliptin is approximately 30%. high-fat meal reduced max by 15% and increased AUC by 4%; this effect is notclinically relevant. Linagliptin may be administered with or withoutfood. Distribution. The mean apparent volumeof distribution at steady state following single intravenous doseof linagliptin mg to healthy subjects is approximately 1110 L, indicatingthat linagliptin extensively distributes to the tissues. Plasma proteinbinding of linagliptin is concentration-dependent, decreasing fromabout 99% at nmol/L to 75%-89% at >=30 nmol/L, reflecting saturationof 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% isunbound 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 Impairment. An open-label pharmacokinetic study evaluated the pharmacokineticsof linagliptin mg in male and female patients with varying degreesof chronic renal impairment. The study included healthy subjectswith normal renal function (creatinine clearance [CrCl] >=80 mL/min),6 patients with mild renal impairment (CrCl 50 to <80 mL/min),6 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 mellitusand normal renal function. Creatinine clearance was measured by 24-hoururinary creatinine clearance measurements or estimated from serumcreatinine based on the Cockcroft-Gault formula.Under steady-state conditions, linagliptin exposurein patients with mild renal impairment was comparable to healthy subjects. In patients with moderate renal impairmentunder steady-state conditions, mean exposure of linagliptin increased(AUC ,ss by 71% and max by 46%) compared with healthy subjects. This increase was not associatedwith prolonged accumulation half-life, terminal half-life, or anincreased accumulation factor. Renal excretion of linagliptin wasbelow 5% of the administered dose and was not affected by decreasedrenal function. Patients withtype diabetes mellitus and severe renal impairment showed steady-stateexposure approximately 40% higher than that of patients with type2 diabetes mellitus and normal renal function (increase in AUC ,ss by 42% and max by 35%).For both type diabetes mellitus groups, renal excretion was below7% of the administered dose. Thesefindings were further supported by the results of population pharmacokineticanalyses.. Hepatic Impairment. In patients with mild hepatic impairment (Child-Pughclass A), steady-state exposure (AUC ,ss) oflinagliptin was approximately 25% lower and max,ss was approximately 36% lower than in healthy subjects. In patientswith moderate hepatic impairment (Child-Pugh class B), AUC ss of linagliptin was about 14% lower and max,ss was approximately 8% lower than in healthy subjects.Patients with severe hepatic impairment (Child-Pugh class C) had comparableexposure of linagliptin in terms of AUC 0-24 and approximately 23% lower max comparedwith healthy subjects. Reductions in the pharmacokinetic parametersseen in patients with hepatic impairment did not result in reductionsin DPP-4 inhibition. Body Mass Index (BMI)/Weight. No dose adjustment is necessary based onBMI/weight. BMI/weight had no clinically meaningful effect on thepharmacokinetics of linagliptin based on population pharmacokineticanalysis.. Gender. No dose adjustment is necessary based on gender. Genderhad no clinically meaningful effect on the pharmacokinetics of linagliptinbased on population pharmacokinetic analysis.. Geriatric. Age did not have clinically meaningful impact on thepharmacokinetics of linagliptin based on population pharmacokineticanalysis.. Pediatric. Studies characterizing the pharmacokinetics of linagliptinin pediatric patients have not yet been performed.. Race. No dose adjustment is necessary based on race. Racehad no clinically meaningful effect on the pharmacokinetics of linagliptinbased on available pharmacokinetic data, including subjects of White,Hispanic, Black, and Asian racial groups.. Drug Interactions. In vitro Assessment of Drug Interactions Linagliptin is weakto moderate inhibitor of CYP isozyme CYP3A4, but does not inhibitother CYP isozymes and is not an inducer of CYP isozymes, includingCYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.Linagliptin is P-glycoprotein (P-gp) substrate, andinhibits P-gp mediated transport of digoxin at high concentrations.Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely tocause interactions with other P-gp substrates at therapeutic concentrations. In vivo Assessment of Drug Interactions Strong inducers ofCYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin tosubtherapeutic and likely ineffective concentrations [see Drug Interactions (7)] In vivo studiesindicated evidence of low propensity for causing drug interactionswith substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationictransporter (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 C max Multiple dose (steady-state) unless otherwise noted For 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 treatments QD once daily BID twice daily TID three times daily Metformin850 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 C max Multiple dose (steady-state) unless otherwise noted Single dose +AUC=AUC(INF) for single-dose treatments and AUC AUC(TAU) for multiple-dose treatments AUC=AUC(0-168) and max=E max for pharmacodynamic end points INR International Normalized Ratio PT Prothrombin Time QD once daily TID three times daily Metformin850 mg TID10 mg QDmetformin1.010.89Glyburide1.75 mg mg QDglyburide0.860.86Pioglitazone45 mg QD10 mg QDpioglitazone metabolite M-III metabolite M-IV 0.94 0.98 1.04 0.86 0.96 1.05 Digoxin0.25 mg QD5 mg QDdigoxin1.020.94Simvastatin40 mg QD10 mg QDsimvastatin simvastatin acid 1.34 1.33 1.10 1.21 Warfarin10 mg mg QDR-warfarin S-warfarin INR PT 0.99 1.03 0.93 1.03 1.00 1.01 1.04 1.15 Ethinylestradiol and levonorgestrelethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD mg QDethinylestradiol levonorgestrel 1.01 1.09 1.08 1.13.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Glycemic Control Trials. Linagliptin has been studied as monotherapy and in combination withmetformin, sulfonylurea, pioglitazone, and insulin. Linagliptin has also been studied in patients with type diabetes and severe chronic renal impairment.In patients with type diabetes, treatmentwith linagliptin produced clinically significant improvements in hemoglobinA1c (A1C), fasting plasma glucose (FPG), and 2-hour post-prandialglucose (PPG) compared with placebo.. MonotherapyA total of 730 patients with type diabetesparticipated in double-blind, placebo-controlled studies, one of18 weeks and another of 24 weeks duration, to evaluate the efficacyand safety of linagliptin monotherapy. In both monotherapy studies,patients currently on an antihyperglycemic agent discontinued theagent and underwent diet, exercise, and drug washout period of about6 weeks that included an open-label placebo run-in during the last2 weeks. Patients with inadequate glycemic control (A1C 7% to 10%)after the washout period were randomized; patients not currently onantihyperglycemic agents (off therapy for at least weeks) with inadequateglycemic control (A1C 7% to 10%) were randomized after completingthe 2-week, open-label, placebo run-in period. In the 18-week study,only patients ineligible for metformin were recruited. In the 18-weekstudy, 76 patients were randomized to placebo and 151 to linagliptin5 mg; in the 24-week study, 167 patients were randomized to placeboand 336 to linagliptin mg. Patients who failed to meet specific glycemicgoals during the 18-week study received rescue therapy with pioglitazoneand/or insulin; metformin rescue therapy was used in the 24-week trial.Treatment with linagliptin mg daily providedstatistically significant improvements in A1C, FPG, and 2-hour PPGcompared with placebo (Table 5). In the 18-week study, 12% of patientsreceiving linagliptin mg and 18% who received placebo required rescuetherapy. In the 24-week study, 10.2% of patients receiving linagliptin5 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 standardindex of insulin resistance (HOMA-IR). As is typical for trials ofagents to treat type diabetes, the mean reduction in A1C with linagliptinappears to be related to the degree of A1C elevation at baseline.In these 18- and 24-week studies, the changes from baseline in A1Cwere -0.4% and -0.4%, respectively, for those given linagliptin, and0.1% and 0.3%, respectively, for those given placebo. Change frombaseline in body weight did not differ significantly between the groups.Table Glycemic Parameters in Placebo-Controlled MonotherapyStudies of LinagliptinFull analysis population using last observation onstudy 18-week study: Placebo, n=68; linagliptin, n=136 24-week study: Placebo, n=147; linagliptin, n=306 18-weekstudy. HbA1c: ANCOVA model included treatment, reason for metforminintolerance 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 intoleranceand number of prior OADs as class-effects, as well as baseline HbA1cand baseline FPG as continuous covariates. 24-week study. HbA1c: ANCOVA model included treatment and number of prior OADs asclass-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment and number of prior OADs asclass-effects, as well as baseline HbA1c and baseline FPG as continuouscovariates. PPG: ANCOVA model included treatment and number of priorOADs as class-effects, as well as baseline HbA1c and baseline postprandialglucose after two hours as covariate. 18-Week Study24-Week StudyLinagliptin mgPlaceboLinagliptin mgPlaceboA1C (%) Number of patientsn 147n 73n 333n 163Baseline (mean)8.18.18.08.0Change from baseline (adjustedmean)-0.40.1-0.40.3Difference from placebo (adjustedmean) (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 (adjustedmean)-137-915Difference from placebo (adjustedmean) (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 (adjustedmean)-----3425Difference from placebo (adjustedmean) (95% CI)-----58 (-82, -34)--. Add-on CombinationTherapy with MetforminA total of 701 patients with type diabetes participatedin 24-week, randomized, double-blind, placebo-controlled study designedto assess the efficacy of linagliptin in combination with metformin. Patients already on metformin (n 491) at dose of at least 1,500mg per day were randomized after completing 2-week, open-label,placebo run-in period. Patients on metformin and another antihyperglycemicagent (n 207) were randomized after run-in period of approximately6 weeks on metformin (at dose of at least 1,500 mg per day) in monotherapy.Patients were randomized to the addition of either linagliptin mgor placebo, administered once daily. Patients who failed to meet specificglycemic goals during the studies were treated with glimepiride rescue.In combination with metformin, linagliptinprovided statistically significant improvements in A1C, FPG, and 2-hourPPG compared with placebo (Table 6). Rescue glycemic therapy wasused in 7.8% of patients treated with linagliptin mg and in 18.9%of patients treated with placebo. similar decrease in body weightwas observed for both treatment groups.Table Glycemic Parameters in Placebo-Controlled Study forLinagliptin in Combination with MetforminFull analysis population using last observation onstudy Linagliptin mg Metformin, n=485; Placebo Metformin,n=163 HbA1c: ANCOVA model included treatment and numberof prior oral OADs as class-effects, as well as baseline HbA1c ascontinuous covariates. FPG: ANCOVA model included treatment andnumber of prior OADs as class-effects, as well as baseline HbA1c andbaseline FPG as continuous covariates. PPG: ANCOVA model includedtreatment and number of prior OADs as class-effects, as well as baselineHbA1c and baseline postprandial glucose after two hours as covariate. Linagliptin mg Metformin Placebo Metformin A1C (%) Number of patientsn 513n 175Baseline (mean)8.18.0Change from baseline (adjustedmean)-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 (adjustedmean)-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 (adjustedmean)-4918Difference from placebo metformin(adjusted mean) (95% CI)-67 (-95, -40)--. Initial CombinationTherapy with MetforminA total of 791 patients with type diabetes mellitusand inadequate glycemic control on diet and exercise participatedin the 24-week, randomized, double-blind, portion of this placebo-controlledfactorial study designed to assess the efficacy of linagliptin as initialtherapy with metformin. Patients on an antihyperglycemic agent (52%)underwent drug washout period of weeks duration. After the washoutperiod and after completing 2-week single-blind placebo run-in period,patients with inadequate glycemic control (A1C >=7.0% to <=10.5%) wererandomized. Patients with inadequate glycemic control (A1C >=7.5% to<11.0%) not on antihyperglycemic agents at study entry (48%) immediatelyentered the 2-week, single-blind, placebo run-in period and then wererandomized. 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 placeboor one of active-treatment arms. Approximately equal numbers ofpatients were randomized to receive initial therapy with mg of linagliptinonce daily, 500 mg or 1,000 mg of metformin twice daily, or 2.5 mgof linagliptin twice daily in combination with 500 mg or 1,000 mg ofmetformin twice daily. Patients who failed to meet specific glycemicgoals during the study were treated with sulfonylurea, thiazolidinedione,or insulin rescue therapy.Initialtherapy with the combination of linagliptin and metformin providedsignificant improvements in A1C and fasting plasma glucose (FPG) comparedto placebo, to metformin alone, and to linagliptin alone (Table 7).The adjusted mean treatment differencein 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 1,000 mg twice dailycompared to metformin 1,000 twice daily; -1.1% (95% CI -1.4, -0.9;p<0.0001) for linagliptin 2.5 mg/metformin 1,000 mg twice dailycompared to linagliptin 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 metformin500 mg twice daily; and -0.8% (95% CI -1.0, -0.6; p<0.0001) forlinagliptin 2.5 mg/metformin 500 mg twice daily compared to linagliptin5 mg once daily.Lipid effectswere generally neutral. No meaningful change in body weight was notedin any of the treatment groups.Table Glycemic Parameters at Final Visit (24-Week Study)for Linagliptin and Metformin, Alone and in Combination in RandomizedPatients with Type Diabetes Mellitus Inadequately Controlled onDiet and ExerciseTotal daily dose of linagliptin is equal to mg Full analysis population using last observation on study Metformin 500 mg twice daily, n=140; Linagliptin 2.5 mg twicedaily Metformin 500 twice daily, n=136; Metformin 1,000 mg twicedaily, n=137; Linagliptin 2.5 mg twice daily Metformin 1,000 mg twicedaily, n=138 HbA1c: ANCOVA model included treatmentand number of prior OADs as class-effects, as well as baseline HbA1cas continuous covariates. FPG: ANCOVA model included treatment andnumber of prior OADs as class-effects, as well as baseline HbA1c andbaseline FPG as continuous covariates. PlaceboLinagliptin mg Once Daily Metformin 500 mg Twice Daily Linagliptin 2.5 mg Twice Daily+ Metformin 500 mg Twice Daily Metformin 1,000 mg Twice Daily Linagliptin 2.5 mg Twice Daily+ Metformin 1,000 mg Twice Daily A1C (%) Number of patientsn 65n 135n 141n 137n 138n 140Baseline (mean)8.78.78.78.78.58.7Change from baseline (adjustedmean)0.1-0.5-0.6-1.2-1.1-1.6Difference from placebo (adjustedmean) (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%7 (10.8)14 (10.4)26 (18.6)41 (30.1)42 (30.7)74 (53.6)Patients (%) receiving rescuemedication29.211.113.57.38.04.3FPG (mg/dL) Number of patientsn 61n 134n 136n 135n 132n 136Baseline (mean)203195191199191196Change from baseline (adjustedmean)10-9-16-33-32-49Difference from placebo (adjustedmean) (95% CI)---19 (-31, -6)-26 (-38, -14)-43 (-56, -31)-42 (-55, -30)-60 (-72, -47). Active-ControlledStudy vs Glimepiride in Combination with MetforminThe efficacy of linagliptin was evaluatedin 104-week, double-blind, glimepiride-controlled, non-inferioritystudy in patients with type diabetes with insufficient glycemiccontrol despite metformin therapy. Patients being treated with metforminonly entered run-in period of weeks duration, whereas patientspretreated with metformin and one additional antihyperglycemic agententered run-in treatment period of weeks duration with metforminmonotherapy (dose of >=1,500 mg/day) and washout of the other agent. After an additional 2-week placebo run-in period, those with inadequateglycemic control (A1C 6.5% to 10%) were randomized 1:1 to the additionof linagliptin mg once daily or glimepiride. Randomization was stratifiedby baseline HbA1c (<8.5% vs >=8.5%), and the previous use of antidiabeticdrugs (metformin alone vs metformin plus one other OAD). Patientsreceiving glimepiride were given an initial dose of mg/day and thenelectively titrated over the next 12 weeks to maximum dose of 4mg/day as needed to optimize glycemic control. Thereafter, the glimepiridedose was to be kept constant, except for down-titration to preventhypoglycemia.After 52 and 104weeks, linagliptin and glimepiride both had reductions from baselinein A1C (52 weeks: -0.4% for linagliptin, -0.6% for glimepiride; 104weeks: -0.2% for linagliptin, -0.4% for glimepiride) from baselinemean of 7.7% (Table 8). The mean difference between groups in A1Cchange from baseline was 0.2% with 2-sided 97.5% confidence interval(0.1%, 0.3%) for the intent-to-treat population using last observationcarried forward. These results were consistent with the completersanalysis.Table Glycemic Parameters at 52 and 104 Weeks in StudyComparing Linagliptin to Glimepiride as Add-On Therapy in Patients InadequatelyControlled on Metforminp<0.0001 vs glimepiride; +p=0.0012 vs glimepiride Full analysis population usinglast observation on study Hypoglycemic incidence includedboth asymptomatic events (not accompanied by typical symptoms andplasma glucose concentration of <=70 mg/dL) and symptomatic eventswith typical symptoms of hypoglycemia and plasma glucose concentrationof <=70 mg/dL. HbA1c: ANCOVA model included treatmentand number of prior OADs as class-effects, as well as baseline HbA1cas continuous covariates. FPG: ANCOVA model included treatment andnumber of prior OADs as class-effects, as well as baseline HbA1c andbaseline FPG as continuous covariates. Hypoglycemia incidence (%): Cochran-Mantel-Haenszel test was performed on the patient populationcontained in the treated set, to compare the proportion of patientswith hypoglycemic events between patients treated with linagliptinand patients treated with glimepiride. Week 52Week 104 Linagliptin 5mg MetforminGlimepiride+ Metformin (mean Glimepiride dose mg) Linagliptin 5mg MetforminGlimepiride+ Metformin (mean Glimepiride dose mg) A1C (%) Number of patientsn 764n 755n 764n 755Baseline (mean)7.77.77.77.7Change from baseline (adjustedmean)-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 (adjustedmean)-8-15-2 -9Hypoglycemiaincidence (%) Number of patientsn 776n 775n 776n 775Incidence5.3 31.17.5 36.1Patients treated with linagliptinhad mean baseline body weight of 86 kg and were observed to havean adjusted mean decrease in body weight of 1.1 kg at 52 weeks and1.4 kg at 104 weeks. Patients on glimepiride had mean baseline bodyweight of 87 kg and were observed to have an adjusted mean increasefrom baseline in body weight of 1.4 kg at 52 weeks and 1.3 kg at 104weeks (treatment difference p<0.0001 for both timepoints).. Add-On CombinationTherapy with PioglitazoneA total of 389 patients with type diabetes participatedin 24-week, randomized, double-blind, placebo-controlled study designedto assess the efficacy of linagliptin in combination with pioglitazone.Therapy was stopped in patients on oral antihyperglycemic therapyfor period of weeks (4 weeks followed by 2-week, open-label,placebo run-in period). Drug-naive patients entered directly intothe 2-week placebo run-in period. After the run-in period, patientswere randomized to receive either linagliptin mg or placebo, bothin addition to pioglitazone 30 mg daily. Patients who failed to meetspecific glycemic goals during the studies were treated with metforminrescue. Glycemic endpoints measured were A1C and FPG.In initial combination with pioglitazone 30 mg, linagliptin5 mg provided statistically significant improvements in A1C and FPGcompared to placebo with pioglitazone (Table 9). Rescue therapy wasused in 7.9% of patients treated with linagliptin mg/pioglitazone30 mg and 14.1% of patients treated with placebo/pioglitazone 30 mg. Patient weight increased in both groups during the study with anadjusted mean change from baseline of 2.3 kg and 1.2 kg in the linagliptin5 mg/pioglitazone 30 mg and placebo/pioglitazone 30 mg groups, respectively(p 0.0141).Table Glycemic Parameters in Placebo-Controlled Study forLinagliptin in Combination Therapy with PioglitazoneFull analysis population using last observation onstudy HbA1c: ANCOVA model included treatment and numberof prior OADs as class-effects, as well as baseline HbA1c as continuouscovariates. FPG: ANCOVA model included treatment and number of priorOADs as class-effects, as well as baseline HbA1c and baseline FPGas continuous covariates. Linagliptin 5mg Pioglitazone Placebo PioglitazoneA1C (%) Number of patientsn 252n 128Baseline (mean)8.68.6Change from baseline (adjustedmean)-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 (adjustedmean)-33-18Difference from placebo pioglitazone(adjusted mean) (95% CI)-14 (-21, -7)--. Add-On Combinationwith SulfonylureasA total of 245 patients with type diabetes participatedin an 18-week, randomized, double-blind, placebo-controlled studydesigned to assess the efficacy of linagliptin in combination with sulfonylurea(SU). Patients on sulfonylurea monotherapy (n 142) were randomizedafter completing 2-week, single-blind, placebo run-in period. Patientson sulfonylurea plus one additional oral antihyperglycemic agent(n 103) were randomized after wash-out period of weeks and a2-week, single-blind, placebo run-in period. Patients were randomizedto the addition of linagliptin mg or to placebo, each administeredonce daily. Patients who failed to meet specific glycemic goals duringthe studies were treated with metformin rescue. Glycemic endpointsmeasured included A1C and FPG.In combination with sulfonylurea, linagliptin provided statisticallysignificant improvements in A1C compared with placebo following 18weeks treatment; the improvements in FPG observed with linagliptinwere not statistically significant compared with placebo (Table 10).Rescue therapy was used in 7.6% of patients treated with linagliptin5 mg and 15.9% of patients treated with placebo. There was no significantdifference between linagliptin and placebo in body weight.Table 10 Glycemic Parameters in Placebo-Controlled Study forLinagliptin in Combination with SulfonylureaSU sulfonylurea Full analysis populationusing last observation on study Linagliptin mg SU,n=156; Placebo SU, n=82 HbA1c: ANCOVA model includedtreatment and number of prior OADs as class-effects, as well as baselineHbA1c as continuous covariates. FPG: ANCOVA model included treatmentand number of prior OADs as class-effects, as well as baseline HbA1cand baseline FPG as continuous covariates Linagliptin mg SUPlacebo SUA1C (%) Number of patientsn 158n 82Baseline (mean)8.68.6Change from baseline (adjustedmean)-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 (adjustedmean)-8-2Difference from placebo SU(adjusted mean) (95% CI)-6 (-17, 4)--. Add-On CombinationTherapy with Metformin and SulfonylureaA total of 1058 patients with type diabetesparticipated in 24-week, randomized, double-blind, placebo-controlledstudy designed to assess the efficacy of linagliptin in combinationwith sulfonylurea and metformin. The most common sulfonylureas usedby patients in the study were: glimepiride (31%), glibenclamide (26%),and gliclazide (26%, not available in the United States). Patientson sulfonylurea and metformin were randomized to receive linagliptin5 mg or placebo, each administered once daily. Patients who failedto meet specific glycemic goals during the study were treated withpioglitazone rescue. Glycemic endpoints measured included A1C andFPG.In combination with sulfonylureaand metformin, linagliptin provided statistically significant improvementsin A1C and FPG compared with placebo (Table 11). In the entire studypopulation (patients on linagliptin in combination with sulfonylureaand metformin), mean reduction from baseline relative to placeboin A1C of -0.6% and in FPG of -13 mg/dL was seen. Rescue therapy wasused in 5.4% of patients treated with linagliptin mg and in 13% ofpatients treated with placebo. Change from baseline in body weightdid not differ significantly between the groups.Table 11 Glycemic Parameters in Placebo-Controlled Studyfor Linagliptin in Combination with Metformin and SulfonylureaSU sulfonylurea Full analysis populationusing last observation on study Linagliptin mg Metformin+ SU, n=742; Placebo Metformin SU, n=247 HbA1c: ANCOVA model included treatment as class-effects and baseline HbA1cas continuous covariates. FPG: ANCOVA model included treatment asclass-effects, as well as baseline HbA1c and baseline FPG as continuouscovariates. Linagliptin 5mg Metformin SUPlacebo Metformin+ SUA1C (%) Number of patientsn 778n 262Baseline (mean)8.28.1Change from baseline (adjustedmean)-0.7-0.1Difference from placebo (adjustedmean) (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 (adjustedmean)-58Difference from placebo (adjustedmean) (95% CI)-13 (-18, -7)--Add-On Combination Therapywith InsulinA total of 1261 patients with type2 diabetes inadequately controlled on basal insulin alone or basalinsulin in combination with oral drugs participated in randomized,double-blind placebo-controlled trial designed to evaluate the efficacyof linagliptin as add-on therapy to basal insulin over 24 weeks. Randomizationwas stratified by baseline HbA1c (<8.5% vs >=8.5%), renal functionimpairment status (based on baseline eGFR), and concomitant use oforal antidiabetic drugs (none, metformin only, pioglitazone only,metformin pioglitazone). Patients with baseline A1C of >7% and <10% were includedin the study including 709 patients with renal impairment (eGFR <90mL/min), most of whom (n=575) were categorized as mild renal impairment(eGFR 60 to <90 mL/min). Patients entered 2 week placebo run-inperiod on basal insulin (e.g., insulin glargine, insulin detemir,or NPH insulin) with or without metformin and/or pioglitazone backgroundtherapy. Following the run-in period, patients with inadequate glycemiccontrol were randomized to the addition of either mg of linagliptinor placebo, administered once daily. Patients were maintained ona stable dose of insulin prior to enrollment, during the run-in period,and during the first 24 weeks of treatment. Patients who failed tomeet specific glycemic goals during the double-blind treatment periodwere rescued by increasing background insulin dose. Linagliptin used in combination with insulin (with orwithout metformin and/or pioglitazone), provided statistically significantimprovements in A1C and FPG compared to placebo (Table 12) after 24weeks of treatment. The mean total daily insulin dose at baselinewas 42 units for patients treated with linagliptin and 40 units forpatients treated with placebo. Background baseline diabetes therapyincluded use of: insulin alone (16.1%), insulin combined with metforminonly (75.5%), insulin combined with metformin and pioglitazone (7.4%),and insulin combined with pioglitazone only (1%). The mean changefrom baseline to Week 24 in the daily dose of insulin was +1.3 IUin the placebo group and +0.6 IU in the linagliptin group. The meanchange in body weight from baseline to Week 24 was similar in thetwo treatment groups. Table 12 Glycemic Parameters in Placebo-Controlled Studyfor Linagliptin in Combination with Insulin Full analysis populationusing last observation carried forward (LOCF) method on study Linagliptin Insulin, n=595; Placebo+ Insulin, n=593 HbA1c: ANCOVA model included treatment,categorical renal function impairment status and concomitant OADsas class-effects, as well as baseline HbA1c as continuous covariates. FPG: ANCOVA model included treatment, categorical renal functionimpairment status and concomitant OADs as class-effects, as well asbaseline HbA1c and baseline FPG as continuous covariates. Linagliptin mg InsulinPlacebo InsulinA1C (%) Number of patientsn 618n 617Baseline (mean)8.38.3Change from baseline (adjustedmean)-0.60.1Difference from placebo (adjustedmean) (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 (adjustedmean)-83Difference from placebo (adjustedmean) (95% CI) -11 (-16, -6)--The difference between treatmentwith linagliptin and placebo in terms of adjusted mean change frombaseline in HbA1c after 24 weeks was comparable for patients withno 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 linagliptin 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, linagliptin 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The pharmacokinetics of linagliptin has been characterized in healthysubjects and patients with type diabetes. After oral administrationof single 5-mg dose to healthy subjects, peak plasma concentrationsof linagliptin occurred at approximately 1.5 hours post dose (T max); the mean plasma area under the curve (AUC) was139 nmolh/L and maximum concentration (C max) was 8.9 nmol/L. Plasma concentrationsof linagliptin decline in at least biphasic manner with long terminalhalf-life (>100 hours), related to the saturable binding of linagliptinto DPP-4. The prolonged elimination phase does not contribute to theaccumulation of the drug. The effective half-life for accumulationof linagliptin, as determined from oral administration of multipledoses of linagliptin mg, is approximately 12 hours. After once-dailydosing, steady-state plasma concentrations of linagliptin mg arereached by the third dose, and max and AUCincreased by factor of 1.3 at steady-state compared with the firstdose. The intra-subject and inter-subject coefficients of variationfor linagliptin AUC were small (12.6% and 28.5%, respectively). PlasmaAUC of linagliptin increased in less than dose-proportional mannerin the dose range of to 10 mg. The pharmacokinetics of linagliptinis similar in healthy subjects and in patients with type diabetes. Absorption. The absolute bioavailabilityof linagliptin is approximately 30%. high-fat meal reduced max by 15% and increased AUC by 4%; this effect is notclinically relevant. Linagliptin may be administered with or withoutfood. Distribution. The mean apparent volumeof distribution at steady state following single intravenous doseof linagliptin mg to healthy subjects is approximately 1110 L, indicatingthat linagliptin extensively distributes to the tissues. Plasma proteinbinding of linagliptin is concentration-dependent, decreasing fromabout 99% at nmol/L to 75%-89% at >=30 nmol/L, reflecting saturationof 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% isunbound 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 Impairment. An open-label pharmacokinetic study evaluated the pharmacokineticsof linagliptin mg in male and female patients with varying degreesof chronic renal impairment. The study included healthy subjectswith normal renal function (creatinine clearance [CrCl] >=80 mL/min),6 patients with mild renal impairment (CrCl 50 to <80 mL/min),6 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 mellitusand normal renal function. Creatinine clearance was measured by 24-hoururinary creatinine clearance measurements or estimated from serumcreatinine based on the Cockcroft-Gault formula.Under steady-state conditions, linagliptin exposurein patients with mild renal impairment was comparable to healthy subjects. In patients with moderate renal impairmentunder steady-state conditions, mean exposure of linagliptin increased(AUC ,ss by 71% and max by 46%) compared with healthy subjects. This increase was not associatedwith prolonged accumulation half-life, terminal half-life, or anincreased accumulation factor. Renal excretion of linagliptin wasbelow 5% of the administered dose and was not affected by decreasedrenal function. Patients withtype diabetes mellitus and severe renal impairment showed steady-stateexposure approximately 40% higher than that of patients with type2 diabetes mellitus and normal renal function (increase in AUC ,ss by 42% and max by 35%).For both type diabetes mellitus groups, renal excretion was below7% of the administered dose. Thesefindings were further supported by the results of population pharmacokineticanalyses.. Hepatic Impairment. In patients with mild hepatic impairment (Child-Pughclass A), steady-state exposure (AUC ,ss) oflinagliptin was approximately 25% lower and max,ss was approximately 36% lower than in healthy subjects. In patientswith moderate hepatic impairment (Child-Pugh class B), AUC ss of linagliptin was about 14% lower and max,ss was approximately 8% lower than in healthy subjects.Patients with severe hepatic impairment (Child-Pugh class C) had comparableexposure of linagliptin in terms of AUC 0-24 and approximately 23% lower max comparedwith healthy subjects. Reductions in the pharmacokinetic parametersseen in patients with hepatic impairment did not result in reductionsin DPP-4 inhibition. Body Mass Index (BMI)/Weight. No dose adjustment is necessary based onBMI/weight. BMI/weight had no clinically meaningful effect on thepharmacokinetics of linagliptin based on population pharmacokineticanalysis.. Gender. No dose adjustment is necessary based on gender. Genderhad no clinically meaningful effect on the pharmacokinetics of linagliptinbased on population pharmacokinetic analysis.. Geriatric. Age did not have clinically meaningful impact on thepharmacokinetics of linagliptin based on population pharmacokineticanalysis.. Pediatric. Studies characterizing the pharmacokinetics of linagliptinin pediatric patients have not yet been performed.. Race. No dose adjustment is necessary based on race. Racehad no clinically meaningful effect on the pharmacokinetics of linagliptinbased on available pharmacokinetic data, including subjects of White,Hispanic, Black, and Asian racial groups.. Drug Interactions. In vitro Assessment of Drug Interactions Linagliptin is weakto moderate inhibitor of CYP isozyme CYP3A4, but does not inhibitother CYP isozymes and is not an inducer of CYP isozymes, includingCYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.Linagliptin is P-glycoprotein (P-gp) substrate, andinhibits P-gp mediated transport of digoxin at high concentrations.Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely tocause interactions with other P-gp substrates at therapeutic concentrations. In vivo Assessment of Drug Interactions Strong inducers ofCYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin tosubtherapeutic and likely ineffective concentrations [see Drug Interactions (7)] In vivo studiesindicated evidence of low propensity for causing drug interactionswith substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationictransporter (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 C max Multiple dose (steady-state) unless otherwise noted For 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 treatments QD once daily BID twice daily TID three times daily Metformin850 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 C max Multiple dose (steady-state) unless otherwise noted Single dose +AUC=AUC(INF) for single-dose treatments and AUC AUC(TAU) for multiple-dose treatments AUC=AUC(0-168) and max=E max for pharmacodynamic end points INR International Normalized Ratio PT Prothrombin Time QD once daily TID three times daily Metformin850 mg TID10 mg QDmetformin1.010.89Glyburide1.75 mg mg QDglyburide0.860.86Pioglitazone45 mg QD10 mg QDpioglitazone metabolite M-III metabolite M-IV 0.94 0.98 1.04 0.86 0.96 1.05 Digoxin0.25 mg QD5 mg QDdigoxin1.020.94Simvastatin40 mg QD10 mg QDsimvastatin simvastatin acid 1.34 1.33 1.10 1.21 Warfarin10 mg mg QDR-warfarin S-warfarin INR PT 0.99 1.03 0.93 1.03 1.00 1.01 1.04 1.15 Ethinylestradiol and levonorgestrelethinylestradiol 0.03 mg and levonorgestrel 0.150 mg QD mg QDethinylestradiol levonorgestrel 1.01 1.09 1.08 1.13.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug Administration.Revised: 6/2020 MEDICATION GUIDE Linagliptin (LIN-a-GLIP-tin) Tablets for oral use Read this Medication Guide carefully before you start taking linagliptin tablets 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 linagliptin tablets, ask your doctor or pharmacist.What is the most important information should know about linagliptin tablets Linagliptin 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 linagliptin tablets, tell your doctor if you have ever had: inflammation of your pancreas (pancreatitis)a history of alcoholismstones in your gallbladder (gallstones)high blood triglyceride levelsStop taking linagliptin tablets 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 linagliptin tablets, 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 linagliptin tabletlinagliptin tablet is prescription medicine used along with diet and exercise to lower blood sugar in adults with type diabetes.linagliptin tablet is not for people with type diabetes.linagliptin tablet 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 linagliptin tablets.It is not known if linagliptin tablet is safe and effective in children under 18 years of age.Who should not take linagliptin tablets Do not take linagliptin tablets if you: are allergic to linagliptin or any of the ingredients in linagliptin tablets. See the end of this Medication Guide for complete list of ingredients in linagliptin tablets. Symptoms of serious allergic reaction to linagliptin tablets 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 linagliptin tablets and call your doctor right away or go to the nearest hospital emergency room. What should tell my doctor before taking linagliptin tablets Before taking linagliptin tablets, 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 linagliptin tablets 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 linagliptin passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take linagliptin tablets.Tell your doctor about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. linagliptin tablets may affect the way other medicines work, and other medicines may affect how linagliptin tablets work. 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 linagliptin tabletsTake linagliptin tablets 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 linagliptin tablets at the same time.Your doctor may tell you to take linagliptin tablets along with other diabetes medicines. Low blood sugar can happen more often when linagliptin tablets are taken with certain other diabetes medicines. See What are the possible side effects of linagliptin tablets If you take too much linagliptin tablets, 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 linagliptin tablets linagliptin tablets may cause serious side effects, including: See What is the most important information should know about linagliptin tablets Low blood sugar (hypoglycemia). If you take linagliptin tablets 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 linagliptin tablets. 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 linagliptin tablets. 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 peelingIf you have any of these symptoms, stop taking linagliptin tablets 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 linagliptin tablets, 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 linagliptin tablets, 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 linagliptin tablets. The most common side effects of linagliptin tablets 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 linagliptin tablets. 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 linagliptin tabletsStore linagliptin tablets at room temperature between 68F and 77F (20C and 25C).Keep linagliptin tablets and all medicines out of the reach of children.General information about the safe and effective use of linagliptin tablets.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use linagliptin tablets for condition for which it was not prescribed. Do not give linagliptin tablets 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 linagliptin tablets that is written for health professionals. What are the ingredients in linagliptin tabletsActive Ingredient: linagliptin Inactive Ingredients: mannitol, pregelatinized starch, copovidone, and magnesium stearate. The film coating contains the following inactive ingredients: hypromellose, titanium dioxide, and polyethylene glycol. Manufactured by: Sunshine Lake Pharma Co., Ltd. Northern Industry Road 1, Song Shan Lake, DongGuan, GuangDong Province, 523808, P.R. China Manufactured for: HEC Pharm USA Inc. 13200 Townsend Road, Philadelphia, PA 19154 The brands listed are trademarks of their respective owners and are not trademarks of HEC Pharm Co., Ltd. The makers of these brands are not affiliated with and do not endorse HEC Pharm Co., Ltd., or its products. 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 linagliptin tablets, 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 linagliptin tablets 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 linagliptin tablets, 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. linagliptin tablet is prescription medicine used along with diet and exercise to lower blood sugar in adults with type diabetes.. linagliptin tablet is not for people with type diabetes.. linagliptin tablet 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 linagliptin tablets.. It is not known if linagliptin tablet is safe and effective in children under 18 years of age.. are allergic to linagliptin or any of the ingredients in linagliptin tablets. See the end of this Medication Guide for complete list of ingredients in linagliptin tablets. Symptoms of serious allergic reaction to linagliptin tablets 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 linagliptin tablets 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 linagliptin passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take linagliptin tablets.. insulin or other medicines that can lower your blood sugar. rifampin (Rifadin, Rimactane, Rifater, Rifamate), an antibiotic that is used to treat tuberculosis. Take linagliptin tablets 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 linagliptin tablets at the same time.. Your doctor may tell you to take linagliptin tablets along with other diabetes medicines. Low blood sugar can happen more often when linagliptin tablets are taken with certain other diabetes medicines. See What are the possible side effects of linagliptin tablets If you take too much linagliptin tablets, 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 linagliptin tablets Low blood sugar (hypoglycemia). If you take linagliptin tablets 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 linagliptin tablets. 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 linagliptin tablets. 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 linagliptin tablets 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 linagliptin tablets, 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 linagliptin tablets, 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 linagliptin tablets. Store linagliptin tablets at room temperature between 68F and 77F (20C and 25C).. logo. logo.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Pancreatitis: There have been reports of acute pancreatitis,including fatal pancreatitis. If pancreatitis is suspected, promptlydiscontinue linagliptin. (5.1) Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of linagliptin 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 secretagogueor insulin to reduce the risk of hypoglycemia (5.3) Hypersensitivity reactions: Serious hypersensitivityreactions (e.g., anaphylaxis,angioedema, and exfoliative skin conditions) have occurred with linagliptin. If hypersensitivity reactions occur, discontinue linagliptin, treat promptly, and monitor until signs and symptoms resolve. (5.4) Arthralgia: Severe and disabling arthralgia has been reported in patientstaking DPP-4 inhibitors. Consider as possible cause for severe jointpain and discontinue drug if appropriate. (5.5) Bullous pemphigoid: There have been reports of bullous pemphigoidrequiring hospitalization. Tell patients to report development of blisters or erosions. If bullouspemphigoid is suspected, discontinue linagliptin (5.6). Pancreatitis: There have been reports of acute pancreatitis,including fatal pancreatitis. If pancreatitis is suspected, promptlydiscontinue linagliptin. (5.1) Heart failure: Heart failure has been observed with two other members of the DPP-4 inhibitor class. Consider risks and benefits of linagliptin 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 secretagogueor insulin to reduce the risk of hypoglycemia (5.3) Hypersensitivity reactions: Serious hypersensitivityreactions (e.g., anaphylaxis,angioedema, and exfoliative skin conditions) have occurred with linagliptin. If hypersensitivity reactions occur, discontinue linagliptin, treat promptly, and monitor until signs and symptoms resolve. (5.4) Arthralgia: Severe and disabling arthralgia has been reported in patientstaking DPP-4 inhibitors. Consider as possible cause for severe jointpain and discontinue drug if appropriate. (5.5) Bullous pemphigoid: There have been reports of bullous pemphigoidrequiring hospitalization. Tell patients to report development of blisters or erosions. If bullouspemphigoid is suspected, discontinue linagliptin (5.6). 5.1 Pancreatitis. Acute pancreatitis, including fatal pancreatitis, has been reported in patients treated with linagliptin.Take careful notice of potential signs and symptomsof pancreatitis. If pancreatitis is suspected, promptly discontinuelinagliptin and initiate appropriate management. It is unknown whetherpatients with history of pancreatitis are at increased risk forthe development of pancreatitis while using linagliptin.. 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 linagliptin 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 linagliptin.. 5.3 Use with MedicationsKnown to Cause Hypoglycemia. Insulin secretagogues and insulin are known to cause hypoglycemia.The use of linagliptin in combination with an insulin secretagogue (e.g.,sulfonylurea) or insulin was associated with higher rate of hypoglycemia comparedwith placebo in clinical trials [see Adverse Reactions (6.1)] The use of linagliptin in combination with insulin in subjects with severe renal impairment was associated with higher rate of hypoglycemia [see Adverse Reactions (6.1)] Therefore,a lower dose of the insulin secretagogue or insulin may be requiredto reduce the risk of hypoglycemia when used in combination with linagliptin. 5.4 HypersensitivityReactions. There have been postmarketing reports of serious hypersensitivityreactions in patients treated with linagliptin. These reactions includeanaphylaxis, angioedema, and exfoliative skin conditions. Onset ofthese reactions predominantly occurred within the first months after initiationof treatment with linagliptin, with some reports occurring after thefirst dose. If serious hypersensitivity reaction is suspected, discontinuelinagliptin, assess for other potential causes for the event, and institutealternative treatment for diabetes. Angioedema has alsobeen reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors.Use caution in patient with history of angioedema to another DPP-4inhibitor because it is unknown whether such patients will be predisposedto angioedema with linagliptin. 5.5 Severe and Disabling Arthralgia. There have been postmarketingreports of severe and disabling arthralgia in patients taking DPP-4inhibitors. The time to onset of symptoms following initiation ofdrug therapy varied from one day to years. Patients experienced reliefof symptoms upon discontinuation of the medication. subset of patientsexperienced recurrence of symptoms when restarting the same drugor different DPP-4 inhibitor. Consider DPP-4 inhibitors as possiblecause for severe joint pain and discontinue drug if appropriate.. 5.6 BullousPemphigoid. Postmarketing cases of bullous pemphigoid requiringhospitalization have been reported with DPP-4 inhibitor use. In reportedcases, patients typically recovered with topical or systemic immunosuppressivetreatment and discontinuation of the DPP-4 inhibitor. Tell patientsto report development of blisters or erosions while receiving linagliptin.If bullous pemphigoid is suspected, linagliptin should be discontinuedand referral to dermatologist should be considered for diagnosisand appropriate treatment.