PHARMACOKINETICS SECTION.


12.3 Pharmacokinetics. JENTADUETOThe resultsof bioequivalence study in healthy subjects demonstrated that JENTADUETO(linagliptin/metformin hydrochloride) 2.5 mg/500 mg, 2.5 mg/850 mg,and 2.5 mg/1000 mg combination tablets are bioequivalent to coadministrationof corresponding doses of linagliptin and metformin as individualtablets. Administration of linagliptin 2.5 mg/metformin hydrochloride1000 mg fixed-dose combination with food resulted in no change inoverall exposure of linagliptin. There was no change in metforminAUC; however, mean peak serum concentration of metformin was decreasedby 18% when administered with food. delayed time-to-peak serum concentrationsby hours was observed for metformin under fed conditions. Thesechanges are not likely to be clinically significant.AbsorptionLinagliptinThe absolute bioavailability of linagliptin is approximately30%. Following oral administration, plasma concentrations of linagliptindecline in at least biphasic manner with long terminal half-life(>100 hours), related to the saturable binding of linagliptin to DPP-4. However, the prolonged elimination does not contribute to the accumulationof the drug. The effective half-life for accumulation of linagliptin,as determined from oral administration of multiple doses of linagliptin5 mg, is approximately 12 hours. After once-daily dosing, steady stateplasma concentrations of linagliptin mg are reached by the thirddose, and Cmax and AUC increased by factorof 1.3 at steady-state compared with the first dose. Plasma AUC oflinagliptin increased in less than dose-proportional manner in thedose range of to 10 mg. The pharmacokinetics of linagliptin is similarin healthy subjects and in patients with type diabetes.MetforminThe absolute bioavailability of metforminhydrochloride 500-mg tablet given under fasting conditions is approximately50% to 60%. Studies using single oral doses of metformin tablets 500mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is lackof dose proportionality with increasing doses, which is due to decreasedabsorption rather than an alteration in elimination.DistributionLinagliptinThe mean apparent volume of distribution at steadystate following single intravenous dose of linagliptin mg to healthysubjects is approximately 1110 L, indicating that linagliptin extensivelydistributes to the tissues. Plasma protein binding of linagliptinis concentration-dependent decreasing from about 99% at nmol/L to75% to 89% at >=30 nmol/L, reflecting saturation of binding to DPP-4with increasing concentration of linagliptin. At high concentrations,where DPP-4 is fully saturated, 70% to 80% of linagliptin remainsbound to plasma proteins and 20% to 30% is unbound in plasma. Plasmabinding is not altered in patients with renal or hepatic impairment.MetforminThe apparent volume of distribution (V/F)of metformin following single oral doses of immediate-release metforminhydrochloride tablets 850 mg averaged 654+-358 L. Metformin is negligiblybound to plasma proteins, in contrast to SUs, which are more than90% protein bound. Metformin partitions into erythrocytes, most likelyas function of time. At usual clinical doses and dosing schedulesof metformin tablets, steady-state plasma concentrations of metforminare reached within 24 to 48 hours and are generally <1 mcg/mL.During controlled clinical trials of metformin, maximum metforminplasma levels did not exceed mcg/mL, even at maximum doses.MetabolismLinagliptinFollowing oral administration, the majority(about 90%) of linagliptin is excreted unchanged, indicating thatmetabolism represents minor elimination pathway. small fractionof absorbed linagliptin is metabolized to pharmacologically inactivemetabolite, which shows steady-state exposure of 13.3% relativeto linagliptin.MetforminIntravenous single-dose studiesin normal subjects demonstrate that metformin is excreted unchangedin the urine and does not undergo hepatic metabolism (no metaboliteshave been identified in humans) nor biliary excretion.ExcretionLinagliptinFollowing administration of an oral [14C]linagliptin dose to healthy subjects, approximately 85% of theadministered radioactivity was eliminated via the enterohepatic system(80%) or urine (5%) within days of dosing. Renal clearance at steadystate was approximately 70 mL/min.MetforminRenal clearance is approximately 3.5 times greater than creatinineclearance, which indicates that tubular secretion is the major routeof metformin elimination. Following oral administration, approximately90% of the absorbed drug is eliminated via the renal route withinthe first 24 hours, with plasma elimination half-life of approximately6.2 hours. In blood, the elimination half-life is approximately 17.6hours, suggesting that the erythrocyte mass may be compartment ofdistribution.SpecificPopulationsRenal ImpairmentJENTADUETO: Studies characterizing the pharmacokineticsof linagliptin and metformin after administration of JENTADUETO inrenally impaired patients have not been performed. Since metforminis contraindicated in patients with renal impairment, use of JENTADUETOis also contraindicated in patients with renal impairment (e.g., serumcreatinine >=1.5 mg/dL [males] or >=1.4 mg/dL [females], or abnormalcreatinine clearance) [see Contraindications (4) and Warnings and Precautions (5.3)]. Linagliptin: Under steady-state conditions,linagliptin exposure in patients with mild renal impairment was comparableto healthy subjects. In patients with moderate renal impairment understeady-state conditions, mean exposure of linagliptin increased (AUC,ss by 71% and Cmax by 46%) comparedwith healthy subjects. This increase was not associated with prolongedaccumulation half-life, terminal half-life, or an increased accumulationfactor. Renal excretion of linagliptin was below 5% of the administereddose and was not affected by decreased renal function.Patients with type diabetes mellitusand severe renal impairment showed steady-state exposure approximately40% higher than that of patients with type diabetes mellitus andnormal renal function (increase in AUC by 42% and Cmax by 35%). For both type diabetes mellitus groups, renal excretionwas below 7% of the administered dose.Metformin: In patients with decreasedrenal function (based on measured creatinine clearance), the plasmaand blood half-life of metformin is prolonged and the renal clearanceis decreased in proportion to the decrease in creatinine clearance [see Contraindications (4) and Warningsand Precautions (5.3)].Hepatic ImpairmentJENTADUETO: Studies characterizing the pharmacokinetics of linagliptin and metforminafter administration of JENTADUETO in hepatically impaired patientshave not been performed. However, use of metformin alone in patientswith hepatic impairment has been associated with some cases of lacticacidosis. Therefore, use of JENTADUETO is not recommended in patientswith hepatic impairment [see Warnings and Precautions (5.4)].Linagliptin: In patients with mildhepatic impairment (Child-Pugh class A) steady-state exposure (AUC,ss) of linagliptin was approximately 25% lower andCmax,ss was approximately 36% lower than inhealthy subjects. In patients with moderate hepatic impairment (Child-Pughclass B), AUCss of linagliptin was about 14%lower and Cmax,ss was approximately 8% lowerthan in healthy subjects. Patients with severe hepatic impairment(Child-Pugh class C) had comparable exposure of linagliptin in termsof AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in thepharmacokinetic parameters seen in patients with hepatic impairmentdid not result in reductions in DPP-4 inhibition.Metformin hydrochloride: No pharmacokineticstudies of metformin have been conducted in patients with hepaticimpairment.Body MassIndex (BMI)/WeightLinagliptin: BMI/Weight had no clinically meaningfuleffect on the pharmacokinetics of linagliptin based on populationpharmacokinetic analysis.GenderLinagliptin: Gender had no clinically meaningful effect on the pharmacokineticsof linagliptin based on population pharmacokinetic analysis.Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantlybetween normal subjects and patients with type diabetes mellituswhen analyzed according to gender. Similarly, in controlled clinicalstudies in patients with type diabetes mellitus, the antihyperglycemiceffect of metformin was comparable in males and females.GeriatricJENTADUETO: Studies characterizingthe pharmacokinetics of linagliptin and metformin after administrationof JENTADUETO in geriatric patients have not been performed. Basedon the metformin component, JENTADUETO treatment should not be initiatedin patients >=80 years of age unless measurement of creatinine clearancedemonstrates that renal function is not reduced [see Warningsand Precautions (5.1, 5.3) and Use in Specific Populations (8.5)]. Linagliptin: Age did not have clinicallymeaningful impact on the pharmacokinetics of linagliptin based ona population pharmacokinetic analysis.Metformin hydrochloride: Limited datafrom controlled pharmacokinetic studies of metformin in healthy elderlysubjects suggest that total plasma clearance of metformin is decreased,the half-life is prolonged, and Cmax is increased,compared with healthy young subjects. From these data, it appearsthat the change in metformin pharmacokinetics with aging is primarilyaccounted for by change in renal function.PediatricStudies characterizing the pharmacokinetics of linagliptinand metformin after administration of JENTADUETO in pediatric patientshave not yet been performed.RaceLinagliptin: Race had no clinically meaningfuleffect on the pharmacokinetics of linagliptin based on available pharmacokineticdata, including subjects of White, Hispanic, Black, and Asian racialgroups.Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to racehave been performed. In controlled clinical studies of metformin inpatients with type diabetes mellitus, the antihyperglycemic effectwas comparable in Caucasians (n=249), Blacks (n=51), and Hispanics(n=24).Drug InteractionsPharmacokinetic drug interactionstudies with JENTADUETO have not been performed; however, such studieshave been conducted with the individual components of JENTADUETO (linagliptinand metformin hydrochloride).LinagliptinIn vitro Assessment of Drug InteractionsLinagliptin is weak to moderate inhibitorof CYP isozyme CYP3A4, but does not inhibit other CYP isozymes andis 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-gpmediated transport of digoxin at high concentrations. Based on theseresults and in vivo drug interaction studies, linagliptinis considered unlikely to cause interactions with other P-gp substratesat therapeutic concentrations.In vivo Assessment of Drug InteractionsStrong inducers of CYP3A4 or P-gp (e.g.,rifampin) decrease exposure to linagliptin to subtherapeutic and likelyineffective concentrations. For patients requiring use of such drugs,an alternative to linagliptin is strongly recommended. Invivo studies indicated evidence of low propensity for causingdrug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp,and OCT. No dose adjustment of linagliptin is recommended based onresults of the described pharmacokinetic studies.Table Effect of Coadministered Drugs on Systemic Exposureof LinagliptinMultiple dose (steady state) unlessotherwise noted Single dose +AUC AUC(0 to 24 hours) for single-dose treatments and AUC AUC(TAU)for multiple-dose treatmentsQD once daily BID twice dailyTID three times dailyCoadministered Drug Dosing of CoadministeredDrugDosing of Linagliptin GeometricMean Ratio (ratio with/without coadministered drug)No effect=1.0 AUC+ Cmax No dosing adjustmentsrequired for linagliptin when given with the following coadministereddrugs:Metformin 850 mg TID10 mg QD 1.201.03Glyburide 1.75 mg mg QD1.021.01Pioglitazone45 mg QD10 mg QD1.131.07Ritonavir200 mg BID5 mg 2.012.96The efficacy of JENTADUETOmay be reduced when administered in combination with strong inducersof CYP3A4 or P-gp (e.g., rifampin). Use of alternative treatmentsis strongly recommended [see Drug Interactions (7.2)] .Rifampin600 mg QD5 mg QD0.60 0.56Table Effect of Linagliptin on Systemic Exposure of CoadministeredDrugs Multiple dose (steady state) unlessotherwise noted Single dose +AUC AUC(INF) for single-dose treatments and AUC AUC(TAU) formultiple-dose treatments AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic endpoints INR International Normalized Ratio PT Prothrombin Time QD once daily TID= three times daily Coadministered DrugDosing of CoadministeredDrugDosing of LinagliptinGeometricMean Ratio(ratio with/without coadministered drug)No effect=1.0AUC+ Cmax No dosing adjustmentsrequired for the following coadministered drugs:Metformin 850 mg TID10 mg QDmetformin 1.01 0.89 Glyburide 1.75 mg mg QDglyburide 0.86 0.86 Pioglitazone 45 mg QD10 mg QDpioglitazonemetabolite M-IIImetabolite M-IV0.94 0.981.04 0.860.961.05 Digoxin 0.25 mg QD5 mg QDdigoxin 1.02 0.94 Simvastatin 40 mg QD10 mg QDsimvastatin simvastatin acid1.34 1.331.101.21Warfarin 10 mg mg QDR-warfarinS-warfarinINRPT0.991.030.93 1.031.001.011.04 1.15Ethinylestradiol andlevonorgestrelethinylestradiol 0.03 mg andlevonorgestrel0.150 mg QD mg QDethinylestradiollevonorgestrel1.01 1.091.08 1.13 Metformin hydrochlorideTable Effect of Coadministered Drug on Plasma MetforminSystemic Exposure All metformin and coadministereddrugs were given as single doses AUC AUC(INF) Ratio of arithmetic means At steady state withtopiramate 100 mg every 12 hours and metformin 500 mg every 12 hours;AUC AUC0-12hCoadministered DrugDosing of CoadministeredDrugDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No effect=1.0AUC+ Cmax No dosing adjustmentsrequired for the following coadministered drugs:Furosemide 40 mg850 mgmetformin 1.09 1.22Nifedipine 10 mg850 mgmetformin 1.16 1.21 Propranolol 40 mg850 mgmetformin 0.90 0.94 Ibuprofen 400 mg850 mgmetformin 1.05 1.07 Cationic drugs eliminatedby renal tubular secretion may reduce metformin elimination: use withcaution [see Warnings and Precautions (5.3) and Drug Interactions (7.1)]. Cimetidine 400 mg850 mgmetformin 1.40 1.61 Carbonic anhydraseinhibitors may cause metabolic acidosis: use with caution [see Warnings and Precautions (5.1) and Drug Interactions (7.1)] Topiramate 100 mg500 mgmetformin 1.25 1.17 Table Effect of Metformin on Coadministered Drug SystemicExposure All metformin and coadministereddrugs were given as single doses AUC AUC(INF) unlessotherwise noted Ratio of arithmetic means, p-valueof difference <0.05 AUC(0-24 hr) reported Ratio of arithmetic meansCoadministeredDrugDosing ofCoadministered DrugDose ofMetforminGeometricMean Ratio(ratio with/without metformin)Noeffect=1.0 AUC+ Cmax No dosing adjustmentsrequired for the following coadministered drugs:Glyburide mg 500 mgglyburide 0.78 0.63 Furosemide 40 mg850 mgfurosemide 0.87 0.69 Nifedipine 10 mg850 mgnifedipine 1.10 1.08 Propranolol 40 mg850 mgpropranolol 1.01 0.94 Ibuprofen 400 mg850 mgibuprofen 0.97 1.01.

RECENT MAJOR CHANGES SECTION.


Dosage and AdministrationConcomitant Use with an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin (2.2) 9/2013Contraindications (4) 5/2014Warnings and PrecautionsUse with Medications Known to Cause Hypoglycemia (5.5) 9/2013Hypersensitivity Reactions (5.6) 5/2014.

ADVERSE REACTIONS SECTION.


6 ADVERSE REACTIONS. Adverse reactions reported in >=5% of patients treated withJENTADUETO and more commonly than in patients treated with placeboare nasopharyngitis and diarrhea (6.1) Hypoglycemia was more commonly reported in patients treatedwith the combination of JENTADUETO and SU compared with those treatedwith the combination of SU and metformin (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.. Adverse reactions reported in >=5% of patients treated withJENTADUETO and more commonly than in patients treated with placeboare nasopharyngitis and diarrhea (6.1) Hypoglycemia was more commonly reported in patients treatedwith the combination of JENTADUETO and SU compared with those treatedwith the combination of SU and metformin (6.1) 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.Linagliptin/MetforminThe safety of concomitantly administered linagliptin(daily dose mg) and metformin (mean daily dose of approximately1800 mg) has been evaluated in 2816 patients with type diabetesmellitus treated for >=12 weeks in clinical trials.Three placebo-controlled studies with linagliptin +metformin were conducted: studies were 24 weeks in duration, studywas 12 weeks in duration. In the placebo-controlled clinical studies,adverse events which occurred in >=5% of patients receiving linagliptin+ metformin (n=875) and were more common than in patients given placebo+ metformin (n=539) included nasopharyngitis (5.7% vs 4.3%).In 24-week factorial design study, adverseevents reported in >=5% of patients receiving linagliptin metforminand were more common than in patients given placebo are shown in Table1.Table Adverse Reactions Reported in >=5% of Patients Treatedwith Linagliptin Metformin and Greater than with Placebo in 24-weekFactorial-Design StudyPlacebon=72Linagliptin Monotherapyn=142Metformin Monotherapyn=291Combination of Linagliptin with Metforminn=286n (%)n (%)n (%)n (%)Nasopharyngitis1 (1.4)8 (5.6)8 (2.7)18 (6.3)Diarrhea2 (2.8)5 (3.5)11 (3.8)18 (6.3)Other adverse reactions reportedin clinical studies with treatment of linagliptin metformin werehypersensitivity (e.g., urticaria, angioedema, or bronchial hyperreactivity),cough, decreased appetite, nausea, vomiting, pruritus, and pancreatitis.LinagliptinAdverse reactions reported in >=2% of patientstreated with linagliptin mg and more commonly than in patients treatedwith placebo included: nasopharyngitis (7.0% vs 6.1%), diarrhea (3.3%vs 3.0%), and cough (2.1% vs 1.4%).Rates for other adverse reactions for linagliptin mg vs placebowhen linagliptin was used in combination with specific anti-diabeticagents were: urinary tract infection (3.1% vs 0%) and hypertriglyceridemia(2.4% vs 0%) when linagliptin was 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-on to pioglitazone; and constipation(2.1% vs 1%) when linagliptin was used as add-on to basal insulintherapy.Other adverse reactionsreported in clinical studies with treatment of linagliptin monotherapywere hypersensitivity (e.g., urticaria, angioedema, localized skinexfoliation, or bronchial hyperreactivity) and myalgia. 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.MetforminThemost common adverse reactions due to initiation of metformin are diarrhea,nausea/vomiting, flatulence, asthenia, indigestion, abdominal discomfort,and headache.Long-term treatmentwith metformin has been associated with decrease in vitamin B12 absorption which may very rarely result in clinicallysignificant vitamin B12 deficiency (e.g., megaloblasticanemia) [see Warnings and Precautions (5.5)].HypoglycemiaLinagliptin/MetforminIn 24-week factorial designstudy, hypoglycemia was reported in (1.4%) of 286 subjects treatedwith linagliptin metformin, (2.1%) of 291 subjects treated withmetformin, and (1.4%) of 72 subjects treated with placebo. Whenlinagliptin was administered in combination with metformin and sulfonylurea,181 (22.9%) of 792 patients reported hypoglycemia compared with 39(14.8%) of 263 patients administered placebo in combination with metforminand sulfonylurea. Adverse reactions of hypoglycemia were based onall reports of hypoglycemia. concurrent glucose measurement wasnot required or was normal in some patients. Therefore, it is notpossible to conclusively determine that all these reports reflecttrue hypoglycemia.LinagliptinIn thestudy of patients receiving linagliptin as add-on therapy to stabledose of insulin for up to 52 weeks (n=1261), no significant differencein the incidence of investigator reported hypoglycemia, defined asall symptomatic or asymptomatic episodes with self-measured bloodglucose <=70 mg/dL, was noted between the linagliptin- (31.4%) andplacebo- (32.9%) treated groups.Use in Renal Impairment Linagliptin was compared to placebo as add-on to pre-existingantidiabetic therapy over 52 weeks in 133 patients with severe renalimpairment (estimated GFR <30 mL/min). For the initial 12 weeksof the study, background antidiabetic therapy was kept stable andincluded insulin, sulfonylurea, glinides, and pioglitazone. For theremainder of the trial, dose adjustments in antidiabetic backgroundtherapy were allowed.In general,the incidence of adverse events including severe hypoglycemia wassimilar to those reported in other linagliptin trials. The observedincidence of hypoglycemia was higher (linagliptin, 63% compared toplacebo, 49%) due to an increase in asymptomatic hypoglycemic eventsespecially during the first 12 weeks when background glycemic therapieswere kept stable. Ten linagliptin-treated patients (15%) and 11 placebo-treatedpatients (17%) reported at least one episode of confirmed symptomatichypoglycemia (accompanying finger stick glucose <=54 mg/dL). Duringthe same time period, severe hypoglycemic events, defined as an eventrequiring the assistance of another person to actively administercarbohydrate, glucagon or other resuscitative actions, were reportedin (4.4%) linagliptin-treated patients and (4.6%) placebo-treatedpatients. Events that were considered life-threatening or requiredhospitalization were reported in (2.9%) patients on linagliptinand (1.5%) patient on placebo.Renal function as measured by mean eGFR and creatinine clearancedid not change over 52 weeks treatment compared to placebo.Laboratory TestsChanges in laboratory findings were similarin patients treated with linagliptin metformin compared to patientstreated with placebo metformin. Changes in laboratory values thatoccurred more frequently in the linagliptin metformin group and>=1% more than in the placebo group were not detected.No clinically meaningful changes in vital signs wereobserved in patients treated with linagliptin.. 6.2 Postmarketing Experience. The following adverse reactions have beenidentified during postapproval use of linagliptin. Because these reactionsare reported voluntarily from population of uncertain size, it isgenerally not possible to reliably estimate their frequency or establisha causal relationship to drug exposure.Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1.2) andWarnings and Precautions (5.2)] Hypersensitivity reactions including anaphylaxis, angioedema,and exfoliative skin conditions [see Warnings and Precautions (5.6)] Rash. Acute pancreatitis, including fatal pancreatitis [see Indications and Usage (1.2) andWarnings and Precautions (5.2)] Hypersensitivity reactions including anaphylaxis, angioedema,and exfoliative skin conditions [see Warnings and Precautions (5.6)] Rash.

BOXED WARNING SECTION.


WARNING: RISK OF LACTIC ACIDOSIS. Lactic acidosis is rare, but serious, complication that can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. The onset is often subtle, accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate.If acidosis is suspected, JENTADUETO should be discontinued and the patient hospitalized immediately [see Warnings and Precautions (5.1)].. WARNING: RISK OF LACTIC ACIDOSISSee full prescribing information for complete boxed warning.Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. (5.1) Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. (5.1) If acidosis is suspected, discontinue JENTADUETO and hospitalize the patient immediately (5.1) Lactic acidosis can occur due to metformin accumulation. The risk increases with conditions such as renal impairment, sepsis, dehydration, excess alcohol intake, hepatic impairment, and acute congestive heart failure. (5.1) Symptoms include malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. Laboratory abnormalities include low pH, increased anion gap, and elevated blood lactate. (5.1) If acidosis is suspected, discontinue JENTADUETO and hospitalize the patient immediately (5.1).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. JENTADUETO. No animal studieshave been conducted with the combined products in JENTADUETO to evaluatecarcinogenesis, mutagenesis, or impairment of fertility. General toxicitystudies in rats up to 13 weeks were performed with JENTADUETO.The following data are based on the findingsin studies with linagliptin and metformin individually.. Linagliptin. Linagliptin didnot increase the incidence of tumors in male and female rats in a2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of60 mg/kg is approximately 418 times the clinical dose of mg/daybased on AUC exposure. Linagliptin did not increase the incidenceof 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 clinicaldose based on AUC exposure. Higher doses of linagliptin in femalemice (80 mg/kg) increased the incidence of lymphoma at approximately215 times the clinical dose based on AUC exposure.Linagliptin was not mutagenic or clastogenic withor without metabolic activation in the Ames bacterial mutagenicityassay, chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay.In fertility studies in rats, linagliptin had no adverseeffects on early embryonic development, mating, fertility, or bearinglive young up to the highest dose of 240 mg/kg (approximately 943times the clinical dose based on AUC exposure).. Metformin Hydrochloride. Long-term carcinogenicitystudies have been performed in rats (dosing duration of 104 weeks)and mice (dosing duration of 91 weeks) at doses up to and including900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are bothapproximately times the maximum recommended human daily dose of2000 mg/kg/day based on body surface area comparisons. No evidenceof carcinogenicity with metformin was found in either male or femalemice. Similarly, there was no tumorigenic potential observed withmetformin in male rats. There was, however, an increased incidenceof benign stromal uterine polyps in female rats treated with 900 mg/kg/day.There was no evidence of mutagenic potentialof metformin in the following in vitro tests: Amestest (Salmonella typhimurium), gene mutation test(mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes).Results in the in vivo mouse micronucleus test werealso negative. Fertility ofmale or female rats was unaffected by metformin when administeredat doses as high as 600 mg/kg/day, which is approximately timesthe MRHD based on body surface area comparisons.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. JENTADUETOJENTADUETO combines antihyperglycemic agents with complementarymechanisms of action to improve glycemic control in patients withtype diabetes mellitus: linagliptin, dipeptidyl peptidase-4 (DPP-4)inhibitor, and metformin, member of the biguanide class.LinagliptinLinagliptin is an inhibitor of DPP-4, anenzyme 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 anddecreasing the levels of glucagon in the circulation. Both incretinhormones are involved in the physiological regulation of glucose homeostasis.Incretin hormones are secreted at low basal level throughout theday and levels rise immediately after meal intake. GLP-1 and GIP increaseinsulin biosynthesis and secretion from pancreatic beta cells in thepresence 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.MetforminMetformin is an antihyperglycemic agent which improvesglucose tolerance in patients with type diabetes mellitus, loweringboth basal and postprandial plasma glucose. Its pharmacologic mechanismsof action are different from other classes of oral antihyperglycemicagents. Metformin decreases hepatic glucose production, decreasesintestinal absorption of glucose, and improves insulin sensitivityby increasing peripheral glucose uptake and utilization. Unlike SUs,metformin does not produce hypoglycemia in either patients with type2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.10)] and does not cause hyperinsulinemia. With metformin therapy,insulin secretion remains unchanged while fasting insulin levels andday-long plasma insulin response may actually decrease.. 12.2 Pharmacodynamics. LinagliptinLinagliptin binds to DPP-4 in reversible manner and increases theconcentrations of incretin hormones. Linagliptin glucose-dependentlyincreases insulin secretion and lowers glucagon secretion, thus resultingin better regulation of the glucose homeostasis. Linagliptin bindsselectively to DPP-4 and selectively inhibits DPP-4, but not DPP-8or DPP-9 activity in vitro at concentrations approximatingtherapeutic exposures.Cardiac ElectrophysiologyIn randomized, placebo-controlled, active-comparator, 4-way crossoverstudy, 36 healthy subjects were administered single oral dose oflinagliptin mg, linagliptin 100 mg (20 times the recommended dose),moxifloxacin, and placebo. No increase in QTc was observed with eitherthe recommended dose of mg or the 100-mg dose. At the 100-mg dose,peak linagliptin plasma concentrations were approximately 38-foldhigher than the peak concentrations following 5-mg dose.. 12.3 Pharmacokinetics. JENTADUETOThe resultsof bioequivalence study in healthy subjects demonstrated that JENTADUETO(linagliptin/metformin hydrochloride) 2.5 mg/500 mg, 2.5 mg/850 mg,and 2.5 mg/1000 mg combination tablets are bioequivalent to coadministrationof corresponding doses of linagliptin and metformin as individualtablets. Administration of linagliptin 2.5 mg/metformin hydrochloride1000 mg fixed-dose combination with food resulted in no change inoverall exposure of linagliptin. There was no change in metforminAUC; however, mean peak serum concentration of metformin was decreasedby 18% when administered with food. delayed time-to-peak serum concentrationsby hours was observed for metformin under fed conditions. Thesechanges are not likely to be clinically significant.AbsorptionLinagliptinThe absolute bioavailability of linagliptin is approximately30%. Following oral administration, plasma concentrations of linagliptindecline in at least biphasic manner with long terminal half-life(>100 hours), related to the saturable binding of linagliptin to DPP-4. However, the prolonged elimination does not contribute to the accumulationof the drug. The effective half-life for accumulation of linagliptin,as determined from oral administration of multiple doses of linagliptin5 mg, is approximately 12 hours. After once-daily dosing, steady stateplasma concentrations of linagliptin mg are reached by the thirddose, and Cmax and AUC increased by factorof 1.3 at steady-state compared with the first dose. Plasma AUC oflinagliptin increased in less than dose-proportional manner in thedose range of to 10 mg. The pharmacokinetics of linagliptin is similarin healthy subjects and in patients with type diabetes.MetforminThe absolute bioavailability of metforminhydrochloride 500-mg tablet given under fasting conditions is approximately50% to 60%. Studies using single oral doses of metformin tablets 500mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is lackof dose proportionality with increasing doses, which is due to decreasedabsorption rather than an alteration in elimination.DistributionLinagliptinThe mean apparent volume of distribution at steadystate following single intravenous dose of linagliptin mg to healthysubjects is approximately 1110 L, indicating that linagliptin extensivelydistributes to the tissues. Plasma protein binding of linagliptinis concentration-dependent decreasing from about 99% at nmol/L to75% to 89% at >=30 nmol/L, reflecting saturation of binding to DPP-4with increasing concentration of linagliptin. At high concentrations,where DPP-4 is fully saturated, 70% to 80% of linagliptin remainsbound to plasma proteins and 20% to 30% is unbound in plasma. Plasmabinding is not altered in patients with renal or hepatic impairment.MetforminThe apparent volume of distribution (V/F)of metformin following single oral doses of immediate-release metforminhydrochloride tablets 850 mg averaged 654+-358 L. Metformin is negligiblybound to plasma proteins, in contrast to SUs, which are more than90% protein bound. Metformin partitions into erythrocytes, most likelyas function of time. At usual clinical doses and dosing schedulesof metformin tablets, steady-state plasma concentrations of metforminare reached within 24 to 48 hours and are generally <1 mcg/mL.During controlled clinical trials of metformin, maximum metforminplasma levels did not exceed mcg/mL, even at maximum doses.MetabolismLinagliptinFollowing oral administration, the majority(about 90%) of linagliptin is excreted unchanged, indicating thatmetabolism represents minor elimination pathway. small fractionof absorbed linagliptin is metabolized to pharmacologically inactivemetabolite, which shows steady-state exposure of 13.3% relativeto linagliptin.MetforminIntravenous single-dose studiesin normal subjects demonstrate that metformin is excreted unchangedin the urine and does not undergo hepatic metabolism (no metaboliteshave been identified in humans) nor biliary excretion.ExcretionLinagliptinFollowing administration of an oral [14C]linagliptin dose to healthy subjects, approximately 85% of theadministered radioactivity was eliminated via the enterohepatic system(80%) or urine (5%) within days of dosing. Renal clearance at steadystate was approximately 70 mL/min.MetforminRenal clearance is approximately 3.5 times greater than creatinineclearance, which indicates that tubular secretion is the major routeof metformin elimination. Following oral administration, approximately90% of the absorbed drug is eliminated via the renal route withinthe first 24 hours, with plasma elimination half-life of approximately6.2 hours. In blood, the elimination half-life is approximately 17.6hours, suggesting that the erythrocyte mass may be compartment ofdistribution.SpecificPopulationsRenal ImpairmentJENTADUETO: Studies characterizing the pharmacokineticsof linagliptin and metformin after administration of JENTADUETO inrenally impaired patients have not been performed. Since metforminis contraindicated in patients with renal impairment, use of JENTADUETOis also contraindicated in patients with renal impairment (e.g., serumcreatinine >=1.5 mg/dL [males] or >=1.4 mg/dL [females], or abnormalcreatinine clearance) [see Contraindications (4) and Warnings and Precautions (5.3)]. Linagliptin: Under steady-state conditions,linagliptin exposure in patients with mild renal impairment was comparableto healthy subjects. In patients with moderate renal impairment understeady-state conditions, mean exposure of linagliptin increased (AUC,ss by 71% and Cmax by 46%) comparedwith healthy subjects. This increase was not associated with prolongedaccumulation half-life, terminal half-life, or an increased accumulationfactor. Renal excretion of linagliptin was below 5% of the administereddose and was not affected by decreased renal function.Patients with type diabetes mellitusand severe renal impairment showed steady-state exposure approximately40% higher than that of patients with type diabetes mellitus andnormal renal function (increase in AUC by 42% and Cmax by 35%). For both type diabetes mellitus groups, renal excretionwas below 7% of the administered dose.Metformin: In patients with decreasedrenal function (based on measured creatinine clearance), the plasmaand blood half-life of metformin is prolonged and the renal clearanceis decreased in proportion to the decrease in creatinine clearance [see Contraindications (4) and Warningsand Precautions (5.3)].Hepatic ImpairmentJENTADUETO: Studies characterizing the pharmacokinetics of linagliptin and metforminafter administration of JENTADUETO in hepatically impaired patientshave not been performed. However, use of metformin alone in patientswith hepatic impairment has been associated with some cases of lacticacidosis. Therefore, use of JENTADUETO is not recommended in patientswith hepatic impairment [see Warnings and Precautions (5.4)].Linagliptin: In patients with mildhepatic impairment (Child-Pugh class A) steady-state exposure (AUC,ss) of linagliptin was approximately 25% lower andCmax,ss was approximately 36% lower than inhealthy subjects. In patients with moderate hepatic impairment (Child-Pughclass B), AUCss of linagliptin was about 14%lower and Cmax,ss was approximately 8% lowerthan in healthy subjects. Patients with severe hepatic impairment(Child-Pugh class C) had comparable exposure of linagliptin in termsof AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in thepharmacokinetic parameters seen in patients with hepatic impairmentdid not result in reductions in DPP-4 inhibition.Metformin hydrochloride: No pharmacokineticstudies of metformin have been conducted in patients with hepaticimpairment.Body MassIndex (BMI)/WeightLinagliptin: BMI/Weight had no clinically meaningfuleffect on the pharmacokinetics of linagliptin based on populationpharmacokinetic analysis.GenderLinagliptin: Gender had no clinically meaningful effect on the pharmacokineticsof linagliptin based on population pharmacokinetic analysis.Metformin hydrochloride: Metformin pharmacokinetic parameters did not differ significantlybetween normal subjects and patients with type diabetes mellituswhen analyzed according to gender. Similarly, in controlled clinicalstudies in patients with type diabetes mellitus, the antihyperglycemiceffect of metformin was comparable in males and females.GeriatricJENTADUETO: Studies characterizingthe pharmacokinetics of linagliptin and metformin after administrationof JENTADUETO in geriatric patients have not been performed. Basedon the metformin component, JENTADUETO treatment should not be initiatedin patients >=80 years of age unless measurement of creatinine clearancedemonstrates that renal function is not reduced [see Warningsand Precautions (5.1, 5.3) and Use in Specific Populations (8.5)]. Linagliptin: Age did not have clinicallymeaningful impact on the pharmacokinetics of linagliptin based ona population pharmacokinetic analysis.Metformin hydrochloride: Limited datafrom controlled pharmacokinetic studies of metformin in healthy elderlysubjects suggest that total plasma clearance of metformin is decreased,the half-life is prolonged, and Cmax is increased,compared with healthy young subjects. From these data, it appearsthat the change in metformin pharmacokinetics with aging is primarilyaccounted for by change in renal function.PediatricStudies characterizing the pharmacokinetics of linagliptinand metformin after administration of JENTADUETO in pediatric patientshave not yet been performed.RaceLinagliptin: Race had no clinically meaningfuleffect on the pharmacokinetics of linagliptin based on available pharmacokineticdata, including subjects of White, Hispanic, Black, and Asian racialgroups.Metformin hydrochloride: No studies of metformin pharmacokinetic parameters according to racehave been performed. In controlled clinical studies of metformin inpatients with type diabetes mellitus, the antihyperglycemic effectwas comparable in Caucasians (n=249), Blacks (n=51), and Hispanics(n=24).Drug InteractionsPharmacokinetic drug interactionstudies with JENTADUETO have not been performed; however, such studieshave been conducted with the individual components of JENTADUETO (linagliptinand metformin hydrochloride).LinagliptinIn vitro Assessment of Drug InteractionsLinagliptin is weak to moderate inhibitorof CYP isozyme CYP3A4, but does not inhibit other CYP isozymes andis 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-gpmediated transport of digoxin at high concentrations. Based on theseresults and in vivo drug interaction studies, linagliptinis considered unlikely to cause interactions with other P-gp substratesat therapeutic concentrations.In vivo Assessment of Drug InteractionsStrong inducers of CYP3A4 or P-gp (e.g.,rifampin) decrease exposure to linagliptin to subtherapeutic and likelyineffective concentrations. For patients requiring use of such drugs,an alternative to linagliptin is strongly recommended. Invivo studies indicated evidence of low propensity for causingdrug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp,and OCT. No dose adjustment of linagliptin is recommended based onresults of the described pharmacokinetic studies.Table Effect of Coadministered Drugs on Systemic Exposureof LinagliptinMultiple dose (steady state) unlessotherwise noted Single dose +AUC AUC(0 to 24 hours) for single-dose treatments and AUC AUC(TAU)for multiple-dose treatmentsQD once daily BID twice dailyTID three times dailyCoadministered Drug Dosing of CoadministeredDrugDosing of Linagliptin GeometricMean Ratio (ratio with/without coadministered drug)No effect=1.0 AUC+ Cmax No dosing adjustmentsrequired for linagliptin when given with the following coadministereddrugs:Metformin 850 mg TID10 mg QD 1.201.03Glyburide 1.75 mg mg QD1.021.01Pioglitazone45 mg QD10 mg QD1.131.07Ritonavir200 mg BID5 mg 2.012.96The efficacy of JENTADUETOmay be reduced when administered in combination with strong inducersof CYP3A4 or P-gp (e.g., rifampin). Use of alternative treatmentsis strongly recommended [see Drug Interactions (7.2)] .Rifampin600 mg QD5 mg QD0.60 0.56Table Effect of Linagliptin on Systemic Exposure of CoadministeredDrugs Multiple dose (steady state) unlessotherwise noted Single dose +AUC AUC(INF) for single-dose treatments and AUC AUC(TAU) formultiple-dose treatments AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic endpoints INR International Normalized Ratio PT Prothrombin Time QD once daily TID= three times daily Coadministered DrugDosing of CoadministeredDrugDosing of LinagliptinGeometricMean Ratio(ratio with/without coadministered drug)No effect=1.0AUC+ Cmax No dosing adjustmentsrequired for the following coadministered drugs:Metformin 850 mg TID10 mg QDmetformin 1.01 0.89 Glyburide 1.75 mg mg QDglyburide 0.86 0.86 Pioglitazone 45 mg QD10 mg QDpioglitazonemetabolite M-IIImetabolite M-IV0.94 0.981.04 0.860.961.05 Digoxin 0.25 mg QD5 mg QDdigoxin 1.02 0.94 Simvastatin 40 mg QD10 mg QDsimvastatin simvastatin acid1.34 1.331.101.21Warfarin 10 mg mg QDR-warfarinS-warfarinINRPT0.991.030.93 1.031.001.011.04 1.15Ethinylestradiol andlevonorgestrelethinylestradiol 0.03 mg andlevonorgestrel0.150 mg QD mg QDethinylestradiollevonorgestrel1.01 1.091.08 1.13 Metformin hydrochlorideTable Effect of Coadministered Drug on Plasma MetforminSystemic Exposure All metformin and coadministereddrugs were given as single doses AUC AUC(INF) Ratio of arithmetic means At steady state withtopiramate 100 mg every 12 hours and metformin 500 mg every 12 hours;AUC AUC0-12hCoadministered DrugDosing of CoadministeredDrugDose of MetforminGeometric Mean Ratio(ratio with/without coadministered drug)No effect=1.0AUC+ Cmax No dosing adjustmentsrequired for the following coadministered drugs:Furosemide 40 mg850 mgmetformin 1.09 1.22Nifedipine 10 mg850 mgmetformin 1.16 1.21 Propranolol 40 mg850 mgmetformin 0.90 0.94 Ibuprofen 400 mg850 mgmetformin 1.05 1.07 Cationic drugs eliminatedby renal tubular secretion may reduce metformin elimination: use withcaution [see Warnings and Precautions (5.3) and Drug Interactions (7.1)]. Cimetidine 400 mg850 mgmetformin 1.40 1.61 Carbonic anhydraseinhibitors may cause metabolic acidosis: use with caution [see Warnings and Precautions (5.1) and Drug Interactions (7.1)] Topiramate 100 mg500 mgmetformin 1.25 1.17 Table Effect of Metformin on Coadministered Drug SystemicExposure All metformin and coadministereddrugs were given as single doses AUC AUC(INF) unlessotherwise noted Ratio of arithmetic means, p-valueof difference <0.05 AUC(0-24 hr) reported Ratio of arithmetic meansCoadministeredDrugDosing ofCoadministered DrugDose ofMetforminGeometricMean Ratio(ratio with/without metformin)Noeffect=1.0 AUC+ Cmax No dosing adjustmentsrequired for the following coadministered drugs:Glyburide mg 500 mgglyburide 0.78 0.63 Furosemide 40 mg850 mgfurosemide 0.87 0.69 Nifedipine 10 mg850 mgnifedipine 1.10 1.08 Propranolol 40 mg850 mgpropranolol 1.01 0.94 Ibuprofen 400 mg850 mgibuprofen 0.97 1.01.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES. The coadministrationof linagliptin and metformin has been studied in patients with type2 diabetes mellitus inadequately controlled on diet and exercise andin combination with sulfonylurea.There have been no clinical efficacy studies conducted with JENTADUETO;however, bioequivalence of JENTADUETO to linagliptin and metformincoadministered as individual tablets was demonstrated in healthy subjects. 14.1 Initial CombinationTherapy with Linagliptin and Metformin. 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 asinitial therapy with metformin. Patients on an antihyperglycemic agent(52%) underwent drug washout period of weeks duration. Afterthe washout period and after completing 2-week single-blind placeborun-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 studyentry (48%) immediately entered the 2-week single-blind placebo run-inperiod and then were randomized. Randomization was stratified by baselineA1C (<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 ratioto either placebo or one of active-treatment arms. Approximatelyequal numbers of patients were randomized to receive initial therapywith mg of linagliptin once daily, 500 mg or 1000 mg of metformintwice daily, or 2.5 mg of linagliptin twice daily in combination with500 mg or 1000 mg of metformin twice daily. Patients who failed tomeet specific glycemic goals during the study were treated with sulfonylurea,thiazolidinedione, or insulin rescue therapy. Initial therapy with the combination of linagliptinand metformin provided significant improvements in A1C, and fastingplasma glucose (FPG) compared to placebo, to metformin alone, andto linagliptin alone (Table 6, Figure 1). The adjusted mean treatmentdifference 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 mgtwice daily compared to metformin 1000 mg twice daily; -1.1% (95%CI -1.4, -0.9; p<0.0001) for linagliptin 2.5 mg/metformin 1000mg twice daily compared to linagliptin mg once daily; -0.6% (95%CI -0.8, -0.4; p<0.0001) for linagliptin 2.5 mg/metformin 500 mgtwice 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 mgtwice daily compared to linagliptin mg once daily.Lipid effects were generally neutral. No meaningfulchange in body weight was noted in 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 isequal to mgFull analysis population using last observationon studyMetformin 500 mg twice daily, n=140; Linagliptin2.5 mg twice daily Metformin 500 twice daily, n=136; Metformin 1000mg twice daily, n=137; Linagliptin 2.5 mg twice daily Metformin1000 mg twice daily, n=138.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.PlaceboLinagliptin mgOnce DailyMetformin 500 mgTwice DailyLinagliptin 2.5 mgTwice Daily Metformin 500 mg Twice DailyMetformin1000mgTwice DailyLinagliptin 2.5mgTwice Daily Metformin 1000 mgTwice DailyA1C (%)Number of patientsn=65 n=135 n=141 n=137 n=138 n=140 Baseline (mean)8.7 8.7 8.7 8.7 8.5 8.7 Change from baseline (adjusted mean)0.1 -0.5 -0.6 -1.2 -1.1 -1.6 Difference 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%7 (10.8) 14 (10.4)26 (18.6)41 (30.1)42 (30.7)74 (53.6)Patients (%) receiving rescue medication 29.2 11.1 13.5 7.3 8.0 4.3 FPG (mg/dL)Number of patientsn=61 n=134 n=136 n=135 n=132 n=136 Baseline (mean)203 195 191 199 191 196 Change from baseline (adjusted mean)10 -9 -16 -33 -32 -49 Difference from placebo (adjusted mean) (95%CI) -- -19 (-31, -6)-26 (-38, -14)-43 (-56, -31)-42 (-55, -30)-60 (-72, -47)Figure Adjusted Mean Changefrom Baseline for A1C (%) over 24 Weeks with Linagliptin and Metformin,Alone and in Combination in Patients with Type Diabetes MellitusInadequately Controlled with Diet and Exercise FAS completers. Figure 1. 14.2 Initial Combination Therapy with Linagliptin and Metforminvs Linagliptin in Treatment-Naive Patients. total of 316 patients with type diabetesdiagnosed within the previous 12 months and treatment-naive (no antidiabetictherapy for 12 weeks prior to randomization) and inadequate glycemiccontrol (A1C >=8.5% to <=12.0%) participated in 24-week, randomized,double-blind, study designed to assess the efficacy of linagliptinin combination with metformin vs linagliptin. Patients were randomized(1:1), after 2-week run-in period, to either linagliptin mg plusmetformin (1500 to 2000 mg per day, n=159) or linagliptin mg plusplacebo, (n=157) administered once daily. Patients in the linagliptinand metformin treatment group were up-titrated to maximum tolerateddose of metformin (1000 to 2000 mg per day) over three-week period.Initial therapy with the combinationof linagliptin and metformin provided statistically significant improvementsin A1C compared to linagliptin (Table 7). The mean difference betweengroups in A1C change from baseline was -0.8% with 2-sided 95% confidenceinterval (-1.23%, -0.45%). Table Glycemic Parameters at 24 Weeks in Study ComparingLinagliptin in Combination with Metformin to Linagliptin in Treatment-NaivePatients+p<0.0001 compared tolinagliptin, ++p=0.0054 compared to linagliptinFull analysis set populationA1C: MMRM model included treatment, continuousbaseline A1C, baseline A1C by visit interaction, visit by treatmentinteraction, baseline renal impairment by treatment interaction andbaseline renal impairment by treatment by visit interaction. FPG: MMRM model included treatment, continuous baseline A1C, continuousbaseline FPG, baseline FPG by visit interaction, visit by treatmentinteraction, baseline renal impairment by treatment interaction andbaseline renal impairment by treatment by visit interaction.Linagliptin mg MetforminLinagliptin mg PlaceboA1C (%) Number of patientsn=153n=150Baseline (mean)9.89.9Change from baseline (adjusted mean)-2.9-2Difference from linagliptin (adjustedmean) (95% CI)-0.84+ (-1.23, -0.45)--Patients [n (%)] achieving A1C <7%82 (53.6)45 (30)FPG (mg/dL)Number of patientsn=153n=150Baseline (mean)196198Change from baseline (adjusted mean)-54-35Difference from linagliptin (adjustedmean) (95% CI)-18++ (-31, -5.5)--The adjusted mean changesfor A1C (%) from baseline over time for linagliptin and metforminas compared to linagliptin alone were maintained throughout the 24week treatment period. Using the completers analysis the respectiveadjusted means for A1C (%) changes from baseline for linagliptin andmetformin as compared to linagliptin alone were -1.9 and -1.3 at week6, -2.6 and -1.8 at week 12, -2.7 and -1.9 at week 18, and -2.7 and-1.9 at week 24.Changesin body weight from baseline were not clinically significant in eithertreatment group.. 14.3 Add-On Combination Therapy with Metformin. total of 701 patients with type diabetesparticipated in 24-week, randomized, double-blind, placebo-controlledstudy designed to assess the efficacy of linagliptin in combinationwith metformin. Patients already on metformin (n=491) at dose ofat least 1500 mg per day were randomized after completing 2-weekopen-label placebo run-in period. Patients on metformin and anotherantihyperglycemic agent (n=207) were randomized after run-in periodof approximately weeks on metformin (at dose of at least 1500mg per day) in monotherapy. Patients were randomized to the additionof either linagliptin mg or placebo, administered once daily. Patientswho failed to meet specific glycemic goals during the studies weretreated with glimepiride rescue.In combination with metformin, linagliptin provided statisticallysignificant improvements in A1C, FPG, and 2-hour PPG compared withplacebo (Table 8). Rescue glycemic therapy was used in 7.8% of patientstreated with linagliptin mg and in 18.9% of patients treated withplacebo. similar decrease in body weight was observed for bothtreatment groups.Table Glycemic Parameters in Placebo-Controlled Study forLinagliptin in Combination with Metformin Full analysis population using lastobservation on studyLinagliptin mg Metformin, n=485;Placebo Metformin, n=163.HbA1c: ANCOVA model includedtreatment and number of prior oral OADs as class-effects, as wellas baseline HbA1c as continuous covariates. FPG: ANCOVA model includedtreatment and number of prior OADs as class-effects, as well as baselineHbA1c and baseline FPG as continuous covariates. PPG: ANCOVA modelincluded treatment and number of prior OADs as class-effects, as wellas baseline HbA1c and baseline postprandial glucose after two hoursas covariate.Linagliptin mg MetforminPlacebo MetforminA1C (%) Number of patientsn=513 n=175 Baseline (mean)8.1 8.0 Change from baseline (adjusted mean) -0.5 0.15 Difference from placebo metformin (adjustedmean) (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=495 n=159 Baseline (mean) 169 164 Change from baseline (adjusted mean) -11 11 Difference from placebo metformin (adjustedmean) (95% CI) -21 (-27, -15)-- 2-hour PPG (mg/dL) Number of patientsn=78 n=21 Baseline (mean) 270 274 Change from baseline (adjusted mean) -49 18 Difference from placebo metformin (adjustedmean) (95% CI) -67 (-95, -40)-- 14.4 Active-Controlled Study vs Glimepiride in Combination withMetformin. The efficacyof linagliptin was evaluated in 104-week double-blind, glimepiride-controllednon-inferiority study in type diabetic patients with insufficientglycemic control despite metformin therapy. Patients being treatedwith metformin only entered run-in period of weeks duration,whereas patients pretreated with metformin and one additional antihyperglycemicagent entered run-in treatment period of weeks duration withmetformin monotherapy (dose of >=1500 mg per day) and washout of theother agent. After an additional 2-week placebo run-in period, thosewith inadequate glycemic control (A1C 6.5% to 10%) were randomized1:1 to the addition of linagliptin 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 metforminplus one other OAD). Patients receiving glimepiride were given aninitial dose of mg/day and then electively titrated over the next12 weeks to maximum dose of mg/day as needed to optimize glycemiccontrol. Thereafter, the glimepiride dose was to be kept constant,except for down-titration to prevent hypoglycemia.After 52 weeks and 104 weeks, linagliptin and glimepirideboth had reductions from baseline in A1C (52 weeks: -0.4% for linagliptin,-0.6% for glimepiride; 104 weeks: -0.2% for linagliptin, -0.4% forglimepiride) from baseline mean of 7.7% (Table 9). The mean differencebetween 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 populationusing last observation carried forward. These results were consistentwith the completers analysis.Table Glycemic Parameters at 52 and 104 Weeks in StudyComparing Linagliptin to Glimepiride as Add-On Therapy in PatientsInadequately Controlled on Metforminp<0.0001 vs glimepiride; +p=0.0012 vs glimepirideFull analysispopulation using last observation on studyHbA1c: ANCOVAmodel included treatment and number of prior OADs as class-effects,as well as baseline HbA1c as continuous covariates. FPG: ANCOVAmodel included treatment and number of prior OADs as class-effects,as well as baseline HbA1c and baseline FPG as continuous covariates.Week 52Week104Linagliptin mg MetforminGlimepiride Metformin(mean glimepiride dose mg)Linagliptin mg MetforminGlimepiride Metformin(mean glimepiride dose mg)A1C (%)Number of patientsn=764n=755n=764n=755Baseline (mean)7.7 7.7 7.77.7Change from baseline (adjusted mean)-0.4 -0.6 -0.2 -0.4 Difference 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)164 166164166Change from baseline (adjusted mean)-8-15-2+ -9Patients 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).. 14.5 Add-On Combination Therapy with Metformin and Sulfonylurea A total of 1058 patients with type 2diabetes mellitus participated in 24-week, randomized, double-blind,placebo-controlled study designed to assess the efficacy of linagliptinin combination with sulfonylurea and metformin. The most commonsulfonylureas used by patients in the study were glimepiride (31%),glibenclamide (26%), and gliclazide (26% [not available in the UnitedStates]). Patients on sulfonylurea and metformin were randomizedto receive linagliptin mg or placebo, each administered once daily. Patients who failed to meet specific glycemic goals during the studywere treated with pioglitazone rescue. Glycemic end points measuredincluded A1C and FPG.In combinationwith sulfonylurea and metformin, linagliptin provided statisticallysignificant improvements in A1C and FPG compared with placebo (Table10). In the entire study population (patients on linagliptin in combinationwith sulfonylurea and metformin), mean reduction from baselinerelative 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 linagliptin5 mg and in 13% of patients treated with placebo. Change from baselinein body weight did not differ significantly between the groups.Table 10 Glycemic Parameters at Final Visit (24-Week Study)for Linagliptin in Combination with Metformin and SulfonylureaSU=sulfonylureaFull analysispopulation using last observation on studyLinagliptin5 mg Metformin SU, n=742; Placebo Metformin SU, n=247HbA1c: ANCOVA model included treatment as class-effects andbaseline HbA1c as continuous covariates. FPG: ANCOVA model includedtreatment as class-effects, as well as baseline HbA1c and baselineFPG as continuous covariates.Linagliptin mg Metformin SUPlacebo Metformin SUA1C (%) Number of patientsn=778 n=262 Baseline (mean) 8.2 8.1 Change from baseline (adjusted mean) -0.7 -0.1 Difference 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=739 n=248 Baseline (mean) 159 163 Change from baseline (adjusted mean) -5 Difference from placebo (adjusted mean) (95%CI) -13 (-18, -7)-- 14.6 Add-On Combination Therapy with Insulin. total of 1261 patients with type diabetesinadequately controlled on basal insulin alone or basal insulin incombination with oral drugs participated in randomized, double-blindplacebo-controlled trial designed to evaluate the efficacy of linagliptinas add-on therapy to basal insulin over 24 weeks. Randomization wasstratified by baseline HbA1c (<8.5% vs >=8.5%), renal function impairmentstatus (based on baseline eGFR), and concomitant use of oral antidiabeticdrugs (none, metformin only, pioglitazone only, metformin pioglitazone).Patients with baseline A1C of >7% and <10% were included in the study including 709 patientswith renal impairment (eGFR <90 mL/min), most of whom (n=575) werecategorized 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 withoutmetformin and/or pioglitazone background therapy. Following the run-inperiod, patients with inadequate glycemic control were randomizedto the addition of either mg of linagliptin or placebo, administeredonce daily. Patients were maintained on stable dose of insulinprior to enrollment, during the run-in period, and during the first24 weeks of treatment. Patients who failed to meet specific glycemicgoals during the double-blind treatment period were rescued by increasingbackground insulin dose. Linagliptinused in combination with insulin (with or without metformin and/orpioglitazone), provided statistically significant improvements inA1C and FPG compared to placebo (Table 11) after 24 weeks of treatment. The mean total daily insulin dose at baseline was 42 units for patientstreated with linagliptin 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 combinedwith metformin and pioglitazone (7.4%), and insulin combined withpioglitazone only (1%). The mean change from baseline to Week 24in the daily dose of insulin was +1.3 IU in the placebo group and+0.6 IU in the linagliptin group. The mean change in body weightfrom baseline to Week 24 was similar in the two treatment groups.The rate of hypoglycemia, defined as all symptomatic or asymptomaticepisodes with self measured blood glucose was also similar in bothgroups (21.4% linagliptin; 22.9% placebo) in the first 24 weeks ofthe study.Table 11 Glycemic Parameters in Placebo-Controlled Studyfor Linagliptin in Combination with InsulinFull analysis population using last observation carriedforward (LOCF) method on studyLinagliptin Insulin,n=595; Placebo Insulin, n=593HbA1c: ANCOVA modelincluded treatment, categorical renal function impairment status andconcomitant OADs as class-effects, as well as baseline HbA1c as continuouscovariates. FPG: ANCOVA model included treatment, categorical renalfunction impairment status and concomitant OADs as class-effects,as well as baseline 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 (eGRF >=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).. 14.7 Renal Impairment. total of 133 patients with type diabetes participated in 52week, double-blind, randomized, placebo-controlled trial designedto evaluate the efficacy and safety of linagliptin in patients withboth type diabetes and severe chronic renal impairment. Participantswith an estimated (based on the four variables modified diet in renaldisease [MDRD] equation) GFR value of <30 mL/min were eligibleto participate in the study. Randomization was stratified by baselineHbA1c (<=8% and >8%) and background antidiabetic therapy (insulin orany combination with insulin, SU or glinides as monotherapy and pioglitazoneor any other antidiabetics excluding any other DPP-4 inhibitors). For the initial 12 weeks of the study, background antidiabetic therapywas kept stable and included insulin, sulfonylurea, glinides, andpioglitazone. For the remainder of the trial, dose adjustments inantidiabetic background therapy were allowed. At baseline in thistrial, 62.5% of patients were receiving insulin alone as backgrounddiabetes therapy, and 12.5% were receiving sulfonylurea alone.After 12 weeks of treatment, linagliptin5 mg provided statistically significant improvement in A1C comparedto placebo, with an adjusted mean change of -0.6% compared to placebo(95% confidence interval -0.9, -0.3) based on the analysis using lastobservation carried forward (LOCF). With adjustments in antidiabeticbackground therapy after the initial 12 weeks, efficacy was maintainedfor 52 weeks, with an adjusted mean change from baseline in A1C of-0.7% compared to placebo (95% confidence interval -1.0, -0.4) basedon analysis using LOCF.

CONTRAINDICATIONS SECTION.


4 CONTRAINDICATIONS. JENTADUETO is contraindicated in patients with:Renal impairment (e.g., serum creatinine >=1.5 mg/dL for men, >=1.4 mg/dL for women, or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions (5.1, 5.3)] Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1)] history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] Hypersensitivity to metformin. Renal impairment (e.g., serum creatinine >=1.5 mg/dL for men, >=1.4 mg/dL for women, or abnormal creatinine clearance), which may also result from conditions such as cardiovascular collapse (shock), acute myocardial infarction, and septicemia [see Warnings and Precautions (5.1, 5.3)] Acute or chronic metabolic acidosis, including diabetic ketoacidosis. Diabetic ketoacidosis should be treated with insulin [see Warnings and Precautions (5.1)] A history of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity [see Warnings and Precautions (5.6) and Adverse Reactions (6.1)] Hypersensitivity to metformin. Renal impairment (4) Metabolic acidosis, including diabetic ketoacidosis (4) History of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity (4) Hypersensitivity to metformin (4) Renal impairment (4) Metabolic acidosis, including diabetic ketoacidosis (4) History of hypersensitivity reaction to linagliptin, such as anaphylaxis, angioedema, exfoliative skin conditions, urticaria, or bronchial hyperreactivity (4) Hypersensitivity to metformin (4).

DESCRIPTION SECTION.


11 DESCRIPTION. JENTADUETO tablets contain oral antihyperglycemicdrugs used in the management of type diabetes mellitus: linagliptinand metformin hydrochloride.LinagliptinLinagliptin is an orally-active inhibitor of the dipeptidyl peptidase-4(DPP-4) enzyme.Linagliptin isdescribed 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 formulais:Linagliptin is white to yellowish, not or only slightly hygroscopicsolid substance. It is very slightly soluble in water (0.9 mg/mL). Linagliptin is soluble in methanol (ca. 60 mg/mL), sparingly solublein ethanol (ca. 10 mg/mL), very slightly soluble in isopropanol (<1mg/mL), and very slightly soluble in acetone (ca. mg/mL).Metformin HydrochlorideMetformin hydrochloride (N,N-dimethylimidodicarbonimidic diamide hydrochloride) isnot chemically or pharmacologically related to any other classes oforal antihyperglycemic agents. Metformin hydrochloride is whiteto off-white crystalline compound with molecular formula of C4H11N5oHCland molecular weight of 165.63. Metformin hydrochloride is freelysoluble in water and is practically insoluble in acetone, ether, andchloroform. The pKa of metformin is 12.4. The pH of 1% aqueous solutionof metformin hydrochloride is 6.68. The structural formula is:JENTADUETOJENTADUETO is available for oral administration as tablets containing2.5 mg linagliptin and 500 mg metformin hydrochloride (JENTADUETO2.5 mg/500 mg), 850 mg metformin hydrochloride (JENTADUETO 2.5 mg/850mg) or 1000 mg metformin hydrochloride (JENTADUETO 2.5 mg/1000 mg).Each film-coated tablet of JENTADUETO contains the following inactiveingredients: arginine, corn starch, copovidone, colloidal silicondioxide, magnesium stearate, titanium dioxide, propylene glycol, hypromellose,talc, yellow ferric oxide (2.5 mg/500 mg; 2.5 mg/850 mg) and/or redferric oxide (2.5 mg/850 mg; 2.5 mg/1000 mg).. Linagliptin structure. Metformin structure.

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION. Individualize the starting dose of JENTADUETO based on the patients current regimen (2.1) The maximum recommended dose is 2.5 mg linagliptin/1000 mg metformin twice daily (2.1) Should be given twice daily with meals, with gradual dose escalation to reduce the gastrointestinal side effects due to metformin (2.1) Individualize the starting dose of JENTADUETO based on the patients current regimen (2.1) The maximum recommended dose is 2.5 mg linagliptin/1000 mg metformin twice daily (2.1) Should be given twice daily with meals, with gradual dose escalation to reduce the gastrointestinal side effects due to metformin (2.1) 2.1 Recommended Dosing. The dosage of JENTADUETO should be individualized on the basis of both effectiveness and tolerability, while not exceeding the maximum recommended dose of 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily. JENTADUETO should be given twice daily with meals. Dose escalation should be gradual to reduce the gastrointestinal (GI) side effects associated with metformin use. For available dosage forms and strengths see [Dosage Forms and Strengths (3)].Recommended starting dose:In patients currently not treated with metformin, initiate treatment with 2.5 mg linagliptin/500 mg metformin hydrochloride twice dailyIn patients already treated with metformin, start with 2.5 mg linagliptin and the current dose of metformin taken at each of the two daily meals (e.g., patient on metformin 1000 mg twice daily would be started on 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily with meals).Patients already treated with linagliptin and metformin individual components may be switched to JENTADUETO containing the same doses of each component.No studies have been performed specifically examining the safety and efficacy of JENTADUETO in patients previously treated with other oral antihyperglycemic agents and switched to JENTADUETO. Any change in therapy of type diabetes mellitus should be undertaken with care and appropriate monitoring as changes in glycemic control can occur.. In patients currently not treated with metformin, initiate treatment with 2.5 mg linagliptin/500 mg metformin hydrochloride twice daily. In patients already treated with metformin, start with 2.5 mg linagliptin and the current dose of metformin taken at each of the two daily meals (e.g., patient on metformin 1000 mg twice daily would be started on 2.5 mg linagliptin/1000 mg metformin hydrochloride twice daily with meals).. Patients already treated with linagliptin and metformin individual components may be switched to JENTADUETO containing the same doses of each component.. 2.2 Concomitant Usewith an Insulin Secretagogue (e.g., Sulfonylurea) or with Insulin. When JENTADUETO is usedin combination with an insulin secretagogue (e.g., sulfonylurea) orwith insulin, lower dose of the insulin secretagogue or insulinmay be required to reduce the risk of hypoglycemia [see Warningsand Precautions (5.5)].

DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS. JENTADUETO is combination of linagliptin and metformin hydrochloride. JENTADUETO tablets are available in the following dosage forms and strengths:2.5 mg linagliptin/1000 mg metformin hydrochloride tablets are light pink, oval, biconvex tablets debossed with D2/1000 on one side and the Boehringer Ingelheim logo on the other side. 2.5 mg linagliptin/1000 mg metformin hydrochloride tablets are light pink, oval, biconvex tablets debossed with D2/1000 on one side and the Boehringer Ingelheim logo on the other side. Tablets:2.5 mg linagliptin/500 mg metformin hydrochloride2.5 mg linagliptin/850 mg metformin hydrochloride2.5 mg linagliptin/1000 mg metformin hydrochloride (3).

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS. Cationic drugs eliminated by renal tubular secretion: Mayreduce metformin elimination. Use with caution. (7.1) Strong P-glycoprotein/CYP3A4 inducer: The efficacy of JENTADUETOmay be reduced when administered in combination (e.g., rifampin). Use of alternative treatments is strongly recommended. (7.2) Cationic drugs eliminated by renal tubular secretion: Mayreduce metformin elimination. Use with caution. (7.1) Strong P-glycoprotein/CYP3A4 inducer: The efficacy of JENTADUETOmay be reduced when administered in combination (e.g., rifampin). Use of alternative treatments is strongly recommended. (7.2) 7.1 Drug Interactionswith Metformin. Cationic DrugsCationicdrugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine,quinine, ranitidine, triamterene, trimethoprim, or vancomycin) thatare eliminated by renal tubular secretion theoretically have the potentialfor interaction with metformin by competing for common renal tubulartransport systems. Although such interactions remain theoretical(except for cimetidine), careful patient monitoring and dose adjustmentof JENTADUETO and/or the interfering drug is recommended in patientswho are taking cationic medications that are excreted via the proximalrenal tubular secretory system [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. Carbonic Anhydrase InhibitorsTopiramate or other carbonic anhydraseinhibitors (e.g., zonisamide, acetazolamide or dichlorphenamide) frequentlydecrease serum bicarbonate and induce non-anion gap, hyperchloremicmetabolic acidosis. Concomitant use of these drugs may induce metabolicacidosis. Use these drugs with caution in patients treated with JENTADUETO,as the risk of lactic acidosis may increase [see Warningsand Precautions (5.1) and ClinicalPharmacology (12.3)]. 7.2 Drug Interactionswith Linagliptin. Inducers of P-glycoprotein and CYP3A4 EnzymesRifampin decreased linagliptin exposure,suggesting that the efficacy of linagliptin may be reduced when administeredin combination with strong P-gp inducer or CYP 3A4 inducer. As JENTADUETOis fixed-dose combination of linagliptin and metformin, use of alternativetreatments (not containing linagliptin) is strongly recommended whenconcomitant treatment with strong P-gp or CYP 3A4 inducer is necessary [see Clinical Pharmacology (12.3)].. 7.3 Drugs AffectingGlycemic Control. Certaindrugs tend to produce hyperglycemia and may lead to loss of glycemiccontrol. These drugs include the thiazides and other diuretics, corticosteroids,phenothiazines, thyroid products, estrogens, oral contraceptives,phenytoin, nicotinic acid, sympathomimetics, calcium channel blockingdrugs, and isoniazid. When such drugs are administered to patientreceiving JENTADUETO, the patient should be closely observed to maintainadequate glycemic control [see Clinical Pharmacology (12.3)]. When such drugs are withdrawnfrom patient receiving JENTADUETO, the patient should be observedclosely for hypoglycemia.

GERIATRIC USE SECTION.


8.5 Geriatric Use. Linagliptinis minimally excreted by the kidney; however, metformin is substantiallyexcreted by the kidney. Considering that aging can be associated withreduced renal function, JENTADUETO should be used with caution asage increases [see Warnings and Precautions (5.1, 5.3) and Clinical Pharmacology (12.3)]. LinagliptinThere were 4040 type diabetespatients treated with linagliptin mg from 15 clinical trials oflinagliptin; 1085 (27%) patients were 65 years and over, while 131(3%) were 75 years and over. Of these patients, 2566 were enrolledin 12 double-blind placebo-controlled studies; 591 (23%) were 65 yearsand over, while 82 (3%) were 75 years and over. No overall differencesin safety or effectiveness were observed between patients 65 yearsand over and younger patients. Therefore, no dose adjustment is recommendedin the elderly population. While clinical studies of linagliptin havenot identified differences in response between the elderly and youngerpatients, greater sensitivity of some older individuals cannot beruled out.MetforminControlled clinical studiesof metformin did not include sufficient numbers of elderly patientsto determine whether they respond differently from younger patients,although other reported clinical experience has not identified differencesin responses between the elderly and young patients. The initial andmaintenance dosing of metformin should be conservative in patientswith advanced age, due to the potential for decreased renal functionin this population. Any dose adjustment should be based on carefulassessment of renal function [see Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGEAND HANDLING. JENTADUETO (linagliptin and metformin hydrochloride) tablets 2.5 mg/1000 mg are supplied as follows: Bottles of 60 (NDC 54868-6461-0) StorageStore at 25C (77F); excursions permitted to 15-30C (59-86F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity. Store in safe place out of reach of children.

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE. JENTADUETO is dipeptidyl peptidase-4 (DPP-4) inhibitor and biguanide combination product indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus when treatment with both linagliptin and metformin is appropriate (1.1) Important limitations of use:Not for treatment of type diabetes or diabetic ketoacidosis (1.2) Has not been studied in patients with history of pancreatitis (1.2) Not for treatment of type diabetes or diabetic ketoacidosis (1.2) Has not been studied in patients with history of pancreatitis (1.2) 1.1 Indication. JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus when treatment with both linagliptin and metformin is appropriate [see Dosage and Administration (2.1) and Clinical Studies (14.1)]. 1.2 Important Limitations of Use. JENTADUETO 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.JENTADUETO 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 JENTADUETO [see Warnings and Precautions (5.2)].

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling(Medication Guide)Medication GuideInstruct patientsto read the Medication Guide before starting JENTADUETO therapy andto reread each time the prescription is renewed. Instruct patientsto inform their doctor if they develop any bothersome or unusual symptoms,or if any symptom persists or worsens.Inform patients of the potential risks andbenefits of JENTADUETO and of alternative modes of therapy. Alsoinform patients about the importance of adherence to dietary instructions,regular physical activity, periodic blood glucose monitoring and A1Ctesting, recognition and management of hypoglycemia and hyperglycemia,and assessment for diabetes complications. Advise patients to seekmedical advice promptly during periods of stress such as fever, trauma,infection, or surgery, as medication requirements may change.Lactic AcidosisInform patients of the risks of lactic acidosis due tothe metformin component, its symptoms, and conditions that predisposeto its development [see Warnings and Precautions (5.1)]. Advise patients to discontinueJENTADUETO immediately and to notify their doctor promptly if unexplainedhyperventilation, malaise, myalgia, unusual somnolence, slow or irregularheart beat, sensation of feeling cold (especially in the extremities),or other nonspecific symptoms occur. GI symptoms are common duringinitiation of metformin treatment and may occur during initiationof JENTADUETO therapy; however, advise patients to consult their doctorif they develop unexplained symptoms. Although GI symptoms that occurafter stabilization are unlikely to be drug related, such an occurrenceof symptoms should be evaluated to determine if it may be due to metformin-inducedlactic acidosis or other serious disease.PancreatitisInform patients that acute pancreatitis has been reported duringpostmarketing use of linagliptin. Inform patients that persistentsevere abdominal pain, sometimes radiating to the back, which mayor may not be accompanied by vomiting, is the hallmark symptom ofacute pancreatitis. Instruct patients to discontinue JENTADUETO promptlyand contact their physician if persistent severe abdominal pain occurs [see Warnings and Precautions (5.2)].Monitoring of Renal FunctionInform patientsabout the importance of regular testing of renal function and hematologicalparameters when receiving treatment with JENTADUETO.Instruct patients to inform their doctorthat they are taking JENTADUETO prior to any surgical or radiologicalprocedure, as temporary discontinuation of JENTADUETO may be requireduntil renal function has been confirmed to be normal [seeWarnings and Precautions (5.3)]. HypoglycemiaInform patients thatthe risk of hypoglycemia is increased when JENTADUETO is used in combinationwith an insulin secretagogue (e.g., sulfonylurea), and that lowerdose of the insulin secretagogue may be required to reduce the riskof hypoglycemia [see Warnings and Precautions (5.5)].Hypersensitivity ReactionsInform patients that serious allergic reactions, suchas anaphylaxis, angioedema, and exfoliative skin conditions, havebeen reported during postmarketing use of linagliptin (one of thecomponents of JENTADUETO). If symptoms of allergic reactions (suchas rash, skin flaking or peeling, urticaria, swelling of the skin,or swelling of the face, lips, tongue, and throat that may cause difficultyin breathing or swallowing) occur, patients must stop taking JENTADUETOand seek medical advice promptly [see Warnings and Precautions(5.6)].Missed DoseInstruct patients to take JENTADUETO only as prescribed. If doseis missed, advise patients not to double their next dose.Alcohol IntakeWarn patients against excessive alcohol intake, eitheracute or chronic, while receiving JENTADUETO [see Warningsand Precautions (5.7)].Blood Glucose andA1C MonitoringInform patients that responseto all diabetic therapies should be monitored by periodic measurementsof blood glucose and A1C levels, with goal of decreasing these levelstoward the normal range. A1C monitoring is especially useful for evaluatinglong-term glycemic control.Renal Function and Other HematologicParameters MonitoringInform patients thatinitial and periodic monitoring of hematologic parameters (e.g., hemoglobin/hematocritand red blood cell indices) and renal function (e.g., serum creatinine)should be performed, at least on an annual basis [see Warningsand Precautions (5.3, 5.7)].

MECHANISM OF ACTION SECTION.


12.1 Mechanism of Action. JENTADUETOJENTADUETO combines antihyperglycemic agents with complementarymechanisms of action to improve glycemic control in patients withtype diabetes mellitus: linagliptin, dipeptidyl peptidase-4 (DPP-4)inhibitor, and metformin, member of the biguanide class.LinagliptinLinagliptin is an inhibitor of DPP-4, anenzyme 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 anddecreasing the levels of glucagon in the circulation. Both incretinhormones are involved in the physiological regulation of glucose homeostasis.Incretin hormones are secreted at low basal level throughout theday and levels rise immediately after meal intake. GLP-1 and GIP increaseinsulin biosynthesis and secretion from pancreatic beta cells in thepresence 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.MetforminMetformin is an antihyperglycemic agent which improvesglucose tolerance in patients with type diabetes mellitus, loweringboth basal and postprandial plasma glucose. Its pharmacologic mechanismsof action are different from other classes of oral antihyperglycemicagents. Metformin decreases hepatic glucose production, decreasesintestinal absorption of glucose, and improves insulin sensitivityby increasing peripheral glucose uptake and utilization. Unlike SUs,metformin does not produce hypoglycemia in either patients with type2 diabetes mellitus or normal subjects (except in special circumstances) [see Warnings and Precautions (5.10)] and does not cause hyperinsulinemia. With metformin therapy,insulin secretion remains unchanged while fasting insulin levels andday-long plasma insulin response may actually decrease.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. JENTADUETO. No animal studieshave been conducted with the combined products in JENTADUETO to evaluatecarcinogenesis, mutagenesis, or impairment of fertility. General toxicitystudies in rats up to 13 weeks were performed with JENTADUETO.The following data are based on the findingsin studies with linagliptin and metformin individually.. Linagliptin. Linagliptin didnot increase the incidence of tumors in male and female rats in a2-year study at doses of 6, 18, and 60 mg/kg. The highest dose of60 mg/kg is approximately 418 times the clinical dose of mg/daybased on AUC exposure. Linagliptin did not increase the incidenceof 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 clinicaldose based on AUC exposure. Higher doses of linagliptin in femalemice (80 mg/kg) increased the incidence of lymphoma at approximately215 times the clinical dose based on AUC exposure.Linagliptin was not mutagenic or clastogenic withor without metabolic activation in the Ames bacterial mutagenicityassay, chromosomal aberration test in human lymphocytes, and an in vivo micronucleus assay.In fertility studies in rats, linagliptin had no adverseeffects on early embryonic development, mating, fertility, or bearinglive young up to the highest dose of 240 mg/kg (approximately 943times the clinical dose based on AUC exposure).. Metformin Hydrochloride. Long-term carcinogenicitystudies have been performed in rats (dosing duration of 104 weeks)and mice (dosing duration of 91 weeks) at doses up to and including900 mg/kg/day and 1500 mg/kg/day, respectively. These doses are bothapproximately times the maximum recommended human daily dose of2000 mg/kg/day based on body surface area comparisons. No evidenceof carcinogenicity with metformin was found in either male or femalemice. Similarly, there was no tumorigenic potential observed withmetformin in male rats. There was, however, an increased incidenceof benign stromal uterine polyps in female rats treated with 900 mg/kg/day.There was no evidence of mutagenic potentialof metformin in the following in vitro tests: Amestest (Salmonella typhimurium), gene mutation test(mouse lymphoma cells), or chromosomal aberrations test (human lymphocytes).Results in the in vivo mouse micronucleus test werealso negative. Fertility ofmale or female rats was unaffected by metformin when administeredat doses as high as 600 mg/kg/day, which is approximately timesthe MRHD based on body surface area comparisons.

NURSING MOTHERS SECTION.


8.3 Nursing Mothers. No studiesin lactating animals have been conducted with the combined componentsof JENTADUETO. In studies performed with the individual components,both linagliptin and metformin were secreted in the milk of lactatingrats. It is not known whether linagliptin is excreted in human milk.Metformin is excreted in human milk in low concentrations. Becausethe potential for hypoglycemia in nursing infants may exist, decisionshould be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.

OVERDOSAGE SECTION.


10 OVERDOSAGE. In the eventof an overdose with JENTADUETO, contact the Poison Control Center.Employ the usual supportive measures (e.g., remove unabsorbed materialfrom the gastrointestinal tract, employ clinical monitoring, and institutesupportive treatment) as dictated by the patients clinical status. Removal of linagliptin by hemodialysis or peritoneal dialysis isunlikely. However, metformin is dialyzable with clearance of upto 170 mL/min under good hemodynamic conditions. Therefore, hemodialysismay be useful partly for removal of accumulated metformin from patientsin whom JENTADUETO overdosage is suspected.LinagliptinDuring controlled clinical trials in healthy subjects,with single doses of up to 600 mg of linagliptin (equivalent to 120times the recommended daily dose), there were no dose-related clinicaladverse drug reactions. There is no experience with doses above 600mg in humans.MetforminOverdose of metformin has occurred,including ingestion of amounts greater than 50 grams. Hypoglycemiawas reported in approximately 10% of cases, but no causal associationwith metformin has been established. Lactic acidosis has been reportedin approximately 32% of metformin overdose cases [see BoxedWarning and Warnings and Precautions (5.1)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Jentadueto (linagliptin and metformin hydrochloride) tabletsNDC: 54868-6461. Jentadueto (linagliptin and metformin hydrochloride) tablets.

PEDIATRIC USE SECTION.


8.4 Pediatric Use. Safetyand effectiveness of JENTADUETO in pediatric patients under 18 yearsof age have not been established.

PHARMACODYNULLMICS SECTION.


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

SAFE HANDLING WARNING SECTION.


8.1 Pregnancy. PregnancyCategory BJENTADUETOThere are no adequate and wellcontrolled studies in pregnant women with JENTADUETO or its individualcomponents, and some clinical data is available for metformin whichindicate that the risk for major malformations was not increased whenmetformin is taken during the first trimester in pregnancy. In addition,metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibilityof harm, JENTADUETO should be used during pregnancy only if clearlyneeded.JENTADUETO was not teratogenicwhen administered to Wistar Han rats during the period of organogenesisat doses similar to clinical exposure. At higher maternally toxicdoses (9 and 23 times the clinical dose based on exposure), the metformincomponent of the combination was associated with an increased incidenceof fetal rib and scapula malformations.LinagliptinLinagliptin was not teratogenic when administered topregnant Wistar Han rats and Himalayan rabbits during the period oforganogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively.These doses represent approximately 943 times the clinical dose inrats and 1943 times the clinical dose in rabbits, based on exposure.No functional, behavioral, or reproductive toxicity was observed inoffspring of female Wistar Han rats when administered linagliptinfrom gestation day to lactation day 21 at dose 49 times the maximumrecommended human dose, based on exposure.Linagliptin crosses the placenta into the fetus followingoral dosing in pregnant rats and rabbits.Metformin HydrochlorideMetformin has been studied for embryo-fetaleffects in rat strains and in rabbits. Metformin was not teratogenicin Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to200 mg/kg (2-3 times the clinical dose based on body surface areaor exposure, respectively). At higher maternally toxic doses (9 and23 times the clinical dose based on exposure), an increased incidenceof rib and scapula skeletal malformations was observed in the WistarHan strain. Metformin was not teratogenic in rabbits at doses up to140 mg/kg (similar to clinical dose based on body surface area).Metformin administered to female SpragueDawley rats from gestation day to lactation day 21 up to 600 mg/kg/day(2 times the maximum clinical dose based on body surface area) hadno effect on prenatal or postnatal development of offspring.Metformin crosses the placenta into thefetus in rats and humans.

SPL MEDGUIDE SECTION.


MEDICATION GUIDEJENTADUETO (JEN ta doo toe)(linagliptin and metformin hydrochloride)TabletsRead this Medication Guide carefully before you start taking JENTADUETO 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 JENTADUETO, ask your doctor or pharmacist.What is the most important information should know about JENTADUETOSerious side effects can happen in people taking JENTADUETO, including:Lactic Acidosis. Metformin, one of the medicines in JENTADUETO, can cause rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. Stop taking JENTADUETO and call your doctor right away if you get any of the following symptoms of lactic acidosis: feel very weak or tiredhave unusual (not normal) muscle painhave trouble breathinghave unusual sleepiness or sleep longer than usualhave sudden stomach or intestinal problems with nausea and vomiting or diarrheafeel cold, especially in your arms and legsfeel dizzy or lightheadedhave slow or irregular heart beat You have higher chance of getting lactic acidosis if you: have kidney problems. People whose kidneys are not working properly should not take JENTADUETO.have liver problemshave congestive heart failure that requires treatment with medicinesdrink alcohol very often, or drink lot of alcohol in short-term (binge drinking)get dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids.have certain x-ray tests with dyes or contrast agents that are injected into your bodyhave surgeryhave heart attack, severe infection, or strokeare 80 years of age or older and have not had your kidneys tested 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 JENTADUETO: Tell your doctor if you have ever had:inflammation of your pancreas (pancreatitis)stones in your gallbladder (gallstones)a history of alcoholismhigh blood triglyceride levels Stop taking JENTADUETO 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 through to your back. The pain may happen with or without vomiting. These may be symptoms of pancreatitis.What is JENTADUETOJENTADUETO is prescription medicine that contains diabetes medicines, linagliptin and metformin. JENTADUETO can be used along with diet and exercise to lower blood sugar in adults with type diabetes when treatment with both linagliptin and metformin is appropriate.JENTADUETO is not for people with type diabetes.JENTADUETO 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 JENTADUETO.It is not known if JENTADUETO is safe and effective in children under 18 years of age.Who should not take JENTADUETODo not take JENTADUETO if you:have kidney problemshave condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine).are allergic to linagliptin, metformin, or any of the ingredients in JENTADUETO. See the end of this Medication Guide for complete list of ingredients in JENTADUETO.Symptoms of serious allergic reaction to JENTADUETO 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 JENTADUETO and contact your doctor or go to the nearest hospital emergency room right away.What should tell my doctor before using JENTADUETOBefore you take JENTADUETO, tell your doctor if you:have or have had inflammation of your pancreas (pancreatitis).have kidney problemshave liver problemshave heart problems, including congestive heart failuredrink alcohol very often, or drink lot of alcohol in short term binge drinkingare 80 years of age or older, you should not take JENTADUETO unless your kidneys have been checked and they are normalare going to get an injection of dye or contrast agents for an x-ray procedure. JENTADUETO will need to be stopped for short time. Talk to your doctor about when you should stop JENTADUETO and when you should start JENTADUETO again. See What is the most important information should know about JENTADUETOhave type diabetes. JENTADUETO should not be used to treat people with type diabetes.have any other medical conditionsare pregnant or plan to become pregnant. It is not known if JENTADUETO 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 JENTADUETO passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take JENTADUETO.Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. JENTADUETO may affect the way other medicines work, and other medicines may affect how JENTADUETO works.Especially tell your doctor if you take:other medicines that can lower your blood sugarrifampin (Rifadin(R), Rimactane(R), Rifater(R), Rifamate(R)), an antibiotic that is used to treat tuberculosisAsk your doctor or pharmacist for list of these medicines if you are not sure if your medicine is one that is listed above. Know the medicines you take. Keep list of them and show it to your doctor and pharmacist when you get new medicine.How should take JENTADUETOTake JENTADUETO exactly as your doctor tells you to take it.Take JENTADUETO times each day with meals. Taking JENTADUETO with meals may lower your chance of having an upset stomach.If you miss dose, take it with food 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 doses of JENTADUETO at the same time.If you take too much JENTADUETO, call your doctor or Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away.Your doctor may tell you to take JENTADUETO along with other diabetes medicines. Low blood sugar can happen more often when JENTADUETO is taken with certain other diabetes medicines. See What are the possible side effects of JENTADUETOYou may need to stop taking JENTADUETO for short time. Call your doctor for instructions if you:are dehydrated (have lost too much body fluid). Dehydration can occur if you are sick with severe vomiting, diarrhea, or fever, or if you drink lot less fluid than normal.plan to have surgeryare going to get an injection of dye or contrast agent for an x-ray procedure. See What is the most important information should know about JENTADUETO and Who should not take JENTADUETO When your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these conditions and follow your doctors instructions.Check your blood sugar as your doctor tells you to.Stay on your prescribed diet and exercise program while taking JENTADUETO.Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.Your doctor will do blood tests to check how well your kidneys are working before and during your treatment with JENTADUETO.What are the possible side effects of JENTADUETO tabletsJENTADUETO may cause serious side effects, including:See What is the most important information should know about JENTADUETOlow blood sugar (hypoglycemia).If you take JENTADUETO with another medication 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 JENTADUETO. Signs and symptoms of low blood sugar may include:headacheirritabilitydrowsinesshungerweaknessfast heart beatdizzinesssweatingconfusionfeeling jitteryAllergic (hypersensitivity) reactions.Serious allergic reactions can happen after your first dose or up to months after starting JENTADUETO. Symptoms may include:swelling of your face, lips, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peelingIf you have these symptoms, stop taking JENTADUETO and call your doctor or go to the nearest hospital emergency room right away. The most common side effects of JENTADUETO include:stuffy or runny nose and sore throatdiarrheaThese are not all the possible side effects of JENTADUETO. For more information, ask your doctor or pharmacist.Tell your doctor if you have any side effects that bother you or that do not go away.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store JENTADUETO tabletsStore JENTADUETO between 68F and 77F (20C and 25C).Keep tablets dry.Keep JENTADUETO and all medicines out of the reach of children.General information about the safe and effective use of JENTADUETOMedicines are sometimes prescribed for purposes other than those listed in Medication Guides. Do not use JENTADUETO for condition for which it was not prescribed. Do not give JENTADUETO to other people, even if they have the same symptoms you have. It may harm them.This Medication Guide summarizes the most important information about JENTADUETO. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about JENTADUETO that is written for health professionals.For more information, go to www.jentadueto.com (or scan the code below to go to www.jentadueto.com) or call Boehringer Ingelheim Pharmaceuticals, Inc. at 1-800-542-6257, or (TTY) 1-800-459-9906.What are the ingredients in JENTADUETOActive Ingredients: linagliptin and metformin hydrochlorideInactive Ingredients: arginine, corn starch, copovidone, colloidal silicon dioxide, magnesium stearate, titanium dioxide, propylene glycol, hypromellose, talc.2.5 mg/500 mg and 2.5 mg/850 mg tablets also contain yellow ferric oxide.2.5 mg/850 mg and 2.5 mg/1000 mg tablets also contain red ferric oxide.What is type diabetes Type diabetes is condition in which your body does not make enough insulin, and/or the insulin that your body produces does not work as well as it should. Your body can also make too much sugar. When this happens, sugar (glucose) builds up in the blood. This can lead to serious medical problems.The main goal of treating diabetes is to lower your blood sugar to normal level. High blood sugar can be lowered by diet and exercise, and by certain medicines when necessary.Talk to your doctor about how to prevent, recognize, and take care of low blood sugar (hypoglycemia), high blood sugar (hyperglycemia), and other problems you have because of your diabetes.This Medication Guide has been approved by the U. S. Food and Drug Administration.Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USAMarketed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA and Eli Lilly and Company Indianapolis, IN 46285 USALicensed from: Boehringer Ingelheim International GmbH Ingelheim, GermanyRevised: July 2014Distributed by:Physicians Total Care, Inc.Tulsa, OK 74146The brands listed are trademarks of their respective owners and are not trademarks of Boehringer Ingelheim Pharmaceuticals, Inc. The makers of these brands are not affiliated with and do not endorse Boehringer Ingelheim Pharmaceuticals, Inc., or its products.Copyright (C) 2014 Boehringer Ingelheim International GmbH ALL RIGHTS RESERVEDIT5571JG312014 300661-05IT5645G 302118-04. Lactic Acidosis. Metformin, one of the medicines in JENTADUETO, can cause rare but serious condition called lactic acidosis (a build-up of lactic acid in the blood) that can cause death. Lactic acidosis is medical emergency and must be treated in the hospital. Stop taking JENTADUETO and call your doctor right away if you get any of the following symptoms of lactic acidosis: feel very weak or tiredhave unusual (not normal) muscle painhave trouble breathinghave unusual sleepiness or sleep longer than usualhave sudden stomach or intestinal problems with nausea and vomiting or diarrheafeel cold, especially in your arms and legsfeel dizzy or lightheadedhave slow or irregular heart beat You have higher chance of getting lactic acidosis if you: have kidney problems. People whose kidneys are not working properly should not take JENTADUETO.have liver problemshave congestive heart failure that requires treatment with medicinesdrink alcohol very often, or drink lot of alcohol in short-term (binge drinking)get dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids.have certain x-ray tests with dyes or contrast agents that are injected into your bodyhave surgeryhave heart attack, severe infection, or strokeare 80 years of age or older and have not had your kidneys tested feel very weak or tired. have unusual (not normal) muscle pain. have trouble breathing. have unusual sleepiness or sleep longer than usual. have sudden stomach or intestinal problems with nausea and vomiting or diarrhea. feel cold, especially in your arms and legs. feel dizzy or lightheaded. have slow or irregular heart beat. have kidney problems. People whose kidneys are not working properly should not take JENTADUETO.. have liver problems. have congestive heart failure that requires treatment with medicines. drink alcohol very often, or drink lot of alcohol in short-term (binge drinking). get dehydrated (lose large amount of body fluids). This can happen if you are sick with fever, vomiting, or diarrhea. Dehydration can also happen when you sweat lot with activity or exercise and do not drink enough fluids.. have certain x-ray tests with dyes or contrast agents that are injected into your body. have surgery. have heart attack, severe infection, or stroke. are 80 years of age or older and have not had your kidneys tested 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 JENTADUETO: Tell your doctor if you have ever had:inflammation of your pancreas (pancreatitis)stones in your gallbladder (gallstones)a history of alcoholismhigh blood triglyceride levels inflammation of your pancreas (pancreatitis). stones in your gallbladder (gallstones). history of alcoholism. high blood triglyceride levels. JENTADUETO is prescription medicine that contains diabetes medicines, linagliptin and metformin. JENTADUETO can be used along with diet and exercise to lower blood sugar in adults with type diabetes when treatment with both linagliptin and metformin is appropriate.. JENTADUETO is not for people with type diabetes.. JENTADUETO 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 JENTADUETO.. It is not known if JENTADUETO is safe and effective in children under 18 years of age.. have kidney problems. have condition called metabolic acidosis or diabetic ketoacidosis (increased ketones in the blood or urine).. are allergic to linagliptin, metformin, or any of the ingredients in JENTADUETO. See the end of this Medication Guide for complete list of ingredients in JENTADUETO.Symptoms of serious allergic reaction to JENTADUETO 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).. have kidney problems. have liver problems. have heart problems, including congestive heart failure. drink alcohol very often, or drink lot of alcohol in short term binge drinking. are 80 years of age or older, you should not take JENTADUETO unless your kidneys have been checked and they are normal. are going to get an injection of dye or contrast agents for an x-ray procedure. JENTADUETO will need to be stopped for short time. Talk to your doctor about when you should stop JENTADUETO and when you should start JENTADUETO again. See What is the most important information should know about JENTADUETO. have type diabetes. JENTADUETO should not be used to treat people with type diabetes.. have any other medical conditions. are pregnant or plan to become pregnant. It is not known if JENTADUETO 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 JENTADUETO passes into your breast milk. Talk with your doctor about the best way to feed your baby if you take JENTADUETO.. other medicines that can lower your blood sugar. rifampin (Rifadin(R), Rimactane(R), Rifater(R), Rifamate(R)), an antibiotic that is used to treat tuberculosis. Take JENTADUETO exactly as your doctor tells you to take it.. Take JENTADUETO times each day with meals. Taking JENTADUETO with meals may lower your chance of having an upset stomach.. If you miss dose, take it with food 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 doses of JENTADUETO at the same time.. If you take too much JENTADUETO, call your doctor or Poison Control Center at 1-800-222-1222 or go to the nearest hospital emergency room right away.. Your doctor may tell you to take JENTADUETO along with other diabetes medicines. Low blood sugar can happen more often when JENTADUETO is taken with certain other diabetes medicines. See What are the possible side effects of JENTADUETO. You may need to stop taking JENTADUETO for short time. Call your doctor for instructions if you:are dehydrated (have lost too much body fluid). Dehydration can occur if you are sick with severe vomiting, diarrhea, or fever, or if you drink lot less fluid than normal.plan to have surgeryare going to get an injection of dye or contrast agent for an x-ray procedure. See What is the most important information should know about JENTADUETO and Who should not take JENTADUETO are dehydrated (have lost too much body fluid). Dehydration can occur if you are sick with severe vomiting, diarrhea, or fever, or if you drink lot less fluid than normal.. plan to have surgery. are going to get an injection of dye or contrast agent for an x-ray procedure. See What is the most important information should know about JENTADUETO and Who should not take JENTADUETO. When your body is under some types of stress, such as fever, trauma (such as car accident), infection, or surgery, the amount of diabetes medicine that you need may change. Tell your doctor right away if you have any of these conditions and follow your doctors instructions.. Check your blood sugar as your doctor tells you to.. Stay on your prescribed diet and exercise program while taking JENTADUETO.. Your doctor will check your diabetes with regular blood tests, including your blood sugar levels and your hemoglobin A1C.. Your doctor will do blood tests to check how well your kidneys are working before and during your treatment with JENTADUETO.. See What is the most important information should know about JENTADUETOlow blood sugar (hypoglycemia).If you take JENTADUETO with another medication 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 JENTADUETO. Signs and symptoms of low blood sugar may include:headacheirritabilitydrowsinesshungerweaknessfast heart beatdizzinesssweatingconfusionfeeling jitteryAllergic (hypersensitivity) reactions.Serious allergic reactions can happen after your first dose or up to months after starting JENTADUETO. Symptoms may include:swelling of your face, lips, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peelingIf you have these symptoms, stop taking JENTADUETO and call your doctor or go to the nearest hospital emergency room right away. low blood sugar (hypoglycemia).If you take JENTADUETO with another medication 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 JENTADUETO. Signs and symptoms of low blood sugar may include:headacheirritabilitydrowsinesshungerweaknessfast heart beatdizzinesssweatingconfusionfeeling jittery. headache. irritability. drowsiness. hunger. weakness. fast heart beat. dizziness. sweating. confusion. feeling jittery. Allergic (hypersensitivity) reactions.Serious allergic reactions can happen after your first dose or up to months after starting JENTADUETO. Symptoms may include:swelling of your face, lips, throat, and other areas on your skindifficulty with swallowing or breathingraised, red areas on your skin (hives)skin rash, itching, flaking, or peelingIf you have these symptoms, stop taking JENTADUETO and call your doctor or go to the nearest hospital emergency room right away.. swelling of your face, lips, throat, and other areas on your skin. difficulty with swallowing or breathing. raised, red areas on your skin (hives). skin rash, itching, flaking, or peeling. stuffy or runny nose and sore throat. diarrhea. Store JENTADUETO between 68F and 77F (20C and 25C).. Keep tablets dry.. SCAN HERE.

SPL UNCLASSIFIED SECTION.


1.1 Indication. JENTADUETO tablets are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type diabetes mellitus when treatment with both linagliptin and metformin is appropriate [see Dosage and Administration (2.1) and Clinical Studies (14.1)].

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS. Pregnancy: JENTADUETO tablets should be used during pregnancyonly if clearly needed. (8.1) Nursing mothers: Caution should be exercised when JENTADUETOis administered to nursing woman (8.3) Pregnancy: JENTADUETO tablets should be used during pregnancyonly if clearly needed. (8.1) Nursing mothers: Caution should be exercised when JENTADUETOis administered to nursing woman (8.3) 8.1 Pregnancy. PregnancyCategory BJENTADUETOThere are no adequate and wellcontrolled studies in pregnant women with JENTADUETO or its individualcomponents, and some clinical data is available for metformin whichindicate that the risk for major malformations was not increased whenmetformin is taken during the first trimester in pregnancy. In addition,metformin was not associated with increased perinatal complications. Nevertheless, because these clinical data cannot rule out the possibilityof harm, JENTADUETO should be used during pregnancy only if clearlyneeded.JENTADUETO was not teratogenicwhen administered to Wistar Han rats during the period of organogenesisat doses similar to clinical exposure. At higher maternally toxicdoses (9 and 23 times the clinical dose based on exposure), the metformincomponent of the combination was associated with an increased incidenceof fetal rib and scapula malformations.LinagliptinLinagliptin was not teratogenic when administered topregnant Wistar Han rats and Himalayan rabbits during the period oforganogenesis at doses up to 240 mg/kg and 150 mg/kg, respectively.These doses represent approximately 943 times the clinical dose inrats and 1943 times the clinical dose in rabbits, based on exposure.No functional, behavioral, or reproductive toxicity was observed inoffspring of female Wistar Han rats when administered linagliptinfrom gestation day to lactation day 21 at dose 49 times the maximumrecommended human dose, based on exposure.Linagliptin crosses the placenta into the fetus followingoral dosing in pregnant rats and rabbits.Metformin HydrochlorideMetformin has been studied for embryo-fetaleffects in rat strains and in rabbits. Metformin was not teratogenicin Sprague Dawley rats up to 600 mg/kg or in Wistar Han rats up to200 mg/kg (2-3 times the clinical dose based on body surface areaor exposure, respectively). At higher maternally toxic doses (9 and23 times the clinical dose based on exposure), an increased incidenceof rib and scapula skeletal malformations was observed in the WistarHan strain. Metformin was not teratogenic in rabbits at doses up to140 mg/kg (similar to clinical dose based on body surface area).Metformin administered to female SpragueDawley rats from gestation day to lactation day 21 up to 600 mg/kg/day(2 times the maximum clinical dose based on body surface area) hadno effect on prenatal or postnatal development of offspring.Metformin crosses the placenta into thefetus in rats and humans.. 8.3 Nursing Mothers. No studiesin lactating animals have been conducted with the combined componentsof JENTADUETO. In studies performed with the individual components,both linagliptin and metformin were secreted in the milk of lactatingrats. It is not known whether linagliptin is excreted in human milk.Metformin is excreted in human milk in low concentrations. Becausethe potential for hypoglycemia in nursing infants may exist, decisionshould be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. Safetyand effectiveness of JENTADUETO in pediatric patients under 18 yearsof age have not been established.. 8.5 Geriatric Use. Linagliptinis minimally excreted by the kidney; however, metformin is substantiallyexcreted by the kidney. Considering that aging can be associated withreduced renal function, JENTADUETO should be used with caution asage increases [see Warnings and Precautions (5.1, 5.3) and Clinical Pharmacology (12.3)]. LinagliptinThere were 4040 type diabetespatients treated with linagliptin mg from 15 clinical trials oflinagliptin; 1085 (27%) patients were 65 years and over, while 131(3%) were 75 years and over. Of these patients, 2566 were enrolledin 12 double-blind placebo-controlled studies; 591 (23%) were 65 yearsand over, while 82 (3%) were 75 years and over. No overall differencesin safety or effectiveness were observed between patients 65 yearsand over and younger patients. Therefore, no dose adjustment is recommendedin the elderly population. While clinical studies of linagliptin havenot identified differences in response between the elderly and youngerpatients, greater sensitivity of some older individuals cannot beruled out.MetforminControlled clinical studiesof metformin did not include sufficient numbers of elderly patientsto determine whether they respond differently from younger patients,although other reported clinical experience has not identified differencesin responses between the elderly and young patients. The initial andmaintenance dosing of metformin should be conservative in patientswith advanced age, due to the potential for decreased renal functionin this population. Any dose adjustment should be based on carefulassessment of renal function [see Contraindications (4), Warnings and Precautions (5.3), and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS. Lactic acidosis: Warn against excessive alcohol use. JENTADUETO is not recommended in hepatic impairment or hypoxic states and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. (5.1, 5.3, 5.4, 5.8, 5.9) There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO. (5.2) Temporarily discontinue JENTADUETO in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids (5.3) 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 (2.2, 5.5) There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO) including anaphylaxis, angioedema, and exfoliative skin conditions. In such cases, promptly discontinue JENTADUETO, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.6) Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually (5.7) Macrovascular outcomes: No conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug (5.10) Lactic acidosis: Warn against excessive alcohol use. JENTADUETO is not recommended in hepatic impairment or hypoxic states and is contraindicated in renal impairment. Ensure normal renal function before initiating and at least annually thereafter. (5.1, 5.3, 5.4, 5.8, 5.9) There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO. (5.2) Temporarily discontinue JENTADUETO in patients undergoing radiologic studies with intravascular administration of iodinated contrast materials or any surgical procedures necessitating restricted intake of food and fluids (5.3) 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 (2.2, 5.5) There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO) including anaphylaxis, angioedema, and exfoliative skin conditions. In such cases, promptly discontinue JENTADUETO, assess for other potential causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes. (5.6) Vitamin B12 deficiency: Metformin may lower vitamin B12 levels. Monitor hematologic parameters annually (5.7) Macrovascular outcomes: No conclusive evidence of macrovascular risk reduction with JENTADUETO or any other antidiabetic drug (5.10) 5.1 Lactic Acidosis. MetforminLactic acidosis is serious, metabolic complication that can occur due to metformin accumulation during treatment with JENTADUETO and is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with number of pathophysiologic conditions, including diabetes mellitus, and whenever there is significant tissue hypoperfusion and hypoxemia. Lactic acidosis is characterized by elevated blood lactate levels (>5 mmol/L), decreased blood pH, electrolyte disturbances with an increased anion gap, and an increased lactate/pyruvate ratio. When metformin is implicated as the cause of lactic acidosis, metformin plasma levels of >5 ug/mL are generally found.The reported incidence of lactic acidosis in patients receiving metformin is approximately 0.03 cases/1000 patient-years, (with approximately 0.015 fatal cases/1000 patient-years). In more than 20,000 patient-years exposure to metformin in clinical trials, there were no reports of lactic acidosis. Reported cases have occurred primarily in diabetic patients with significant renal impairment, including both intrinsic renal disease and renal hypoperfusion, often in the setting of multiple concomitant medical/surgical problems and multiple concomitant medications. Patients with congestive heart failure requiring pharmacologic management, particularly when accompanied by hypoperfusion and hypoxemia due to unstable or acute failure, are at increased risk of lactic acidosis. The risk of lactic acidosis increases with the degree of renal impairment and the patients age. The risk of lactic acidosis may, therefore, be significantly decreased by regular monitoring of renal function in patients taking metformin. In particular, treatment of the elderly should be accompanied by careful monitoring of renal function. Metformin treatment should not be initiated in any patient unless measurement of creatinine clearance demonstrates that renal function is not reduced. In addition, metformin should be promptly withheld in the presence of any condition associated with hypoxemia, dehydration, or sepsis. Because impaired hepatic function may significantly limit the ability to clear lactate, metformin should be avoided in patients with clinical or laboratory evidence of hepatic impairment. Patients should be cautioned against excessive alcohol intake when taking metformin, since alcohol potentiates the effects of metformin on lactate metabolism. In addition, metformin should be temporarily discontinued prior to any intravascular radiocontrast study and for any surgical procedure necessitating restricted intake of food or fluids. Use of topiramate, carbonic anhydrase inhibitor, in epilepsy and migraine prophylaxis may cause dose-dependent metabolic acidosis and may exacerbate the risk of metformin-induced lactic acidosis [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].The onset of lactic acidosis is often subtle, and accompanied by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress. More severe acidosis may be associated with signs such as hypothermia, hypotension, and resistant bradyarrhythmias. Patients should be educated to recognize and promptly report these symptoms. If present, JENTADUETO should be discontinued until lactic acidosis is ruled out. Gastrointestinal symptoms, which are commonly reported during initiation of metformin therapy are less frequently observed in subjects on chronic, stable, dose of metformin. Gastrointestinal symptoms in subjects on chronic, stable, dose of metformin could be caused by lactic acidosis or other serious disease.To rule out lactic acidosis, serum electrolytes, ketones, blood glucose, blood pH, lactate levels, and blood metformin levels may be useful. Levels of fasting venous plasma lactate above the upper limit of normal but less than mmol/L in patients taking metformin do not necessarily indicate impending lactic acidosis and may be due to other mechanisms, such as poorly-controlled diabetes or obesity, vigorous physical activity, or technical problems in sample handling.Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia). Lactic acidosis is medical emergency that must be treated in hospital setting. In patient with lactic acidosis who is taking metformin, the drug should be discontinued immediately and supportive measures promptly instituted. Metformin is dialyzable (clearance of up to 170 mL/min under good hemodynamic conditions) and prompt hemodialysis is recommended to remove the accumulated metformin and correct the metabolic acidosis. Such management often results in prompt reversal of symptoms and recovery [see Boxed Warning]. 5.2 Pancreatitis. There have been postmarketing reports of acute pancreatitis, including fatal pancreatitis, in patients taking linagliptin. Take careful notice of potential signs and symptoms of pancreatitis. If pancreatitis is suspected, promptly discontinue JENTADUETO and initiate appropriate management. It is unknown whether patients with history of pancreatitis are at increased risk for the development of pancreatitis while using JENTADUETO.. 5.3 Monitoring of Renal Function. Although linagliptin undergoes minimal renal excretion, metformin is known to be substantially excreted by the kidney. The risk of metformin accumulation and lactic acidosis increases with the degree of renal impairment. Therefore, JENTADUETO is contraindicated in patients with renal impairment.Before initiation of therapy with JENTADUETO and at least annually thereafter, renal function should be assessed and verified to be normal. In patients in whom development of renal impairment is anticipated (e.g., elderly), renal function should be assessed more frequently and JENTADUETO discontinued if evidence of renal impairment is present.Linagliptin may be continued as single entity tablet at the same total daily dose of mg if JENTADUETO is discontinued due to evidence of renal impairment. No dose adjustment of linagliptin is recommended in patients with renal impairment.Use of concomitant medications that may affect renal function or metformin disposition:Concomitant medication(s) that may affect renal function or result in significant hemodynamic change or interfere with the disposition of metformin should be used with caution [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].Radiological studies and surgical procedures:Radiologic studies involving the use of intravascular iodinated contrast materials (e.g., intravenous urogram, intravenous cholangiography, angiography, and computed tomography) can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin. Therefore, in patients in whom any such study is planned, JENTADUETO should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been confirmed to be normal.JENTADUETO should be temporarily discontinued for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patients oral intake has resumed and renal function has been evaluated as normal.. 5.4 Impaired Hepatic Function. Because impaired hepatic function has been associated with some cases of lactic acidosis with metformin therapy, JENTADUETO should generally be avoided in patients with clinical or laboratory evidence of hepatic disease [see Warnings and Precautions (5.1)]. 5.5 Use with Medications Known to Cause Hypoglycemia. LinagliptinInsulin secretagogues and insulin are known to cause hypoglycemia. The use of linagliptin in combination with an insulin secretagogue (e.g., sulfonylurea) was associated with higher rate of hypoglycemia compared with placebo in clinical trial [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, lower dose of the insulin secretagogue or insulin may be required to reduce the risk of hypoglycemia when used in combination with JENTADUETO [see Dosage and Administration (2.2)]. MetforminHypoglycemia does not occur in patients receiving metformin alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as SUs and insulin) or ethanol. Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycemia may be difficult to recognize in the elderly, and in people who are taking -adrenergic blocking drugs.. 5.6 Hypersensitivity Reactions. There have been postmarketing reports of serious hypersensitivity reactions in patients treated with linagliptin (one of the components of JENTADUETO). These reactions include anaphylaxis, angioedema, and exfoliative skin conditions. Onset of these reactions occurred within the first months after initiation of treatment with linagliptin, with some reports occurring after the first dose. If serious hypersensitivity reaction is suspected, discontinue JENTADUETO, 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 JENTADUETO.. 5.7 Vitamin B12 Levels. In controlled, 29-week clinical trials of metformin, decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, was observed in approximately 7% of metformin-treated patients. Such decrease, possibly due to interference with B12 absorption from the B12-intrinsic factor complex, is, however, very rarely associated with anemia or neurologic manifestations due to the short duration (<1 year) of the clinical trials. This risk may be more relevant to patients receiving long-term treatment with metformin, and adverse hematologic and neurologic reactions have been reported postmarketing. The decrease in vitamin B12 levels appears to be rapidly reversible with discontinuation of metformin or vitamin B12 supplementation. Measurement of hematologic parameters on an annual basis is advised in patients on JENTADUETO and any apparent abnormalities should be appropriately investigated and managed. Certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels. In these patients, routine serum vitamin B12 measurement at 2- to 3-year intervals may be useful.. 5.8 Alcohol Intake. Alcohol is known to potentiate the effect of metformin on lactate metabolism. Patients, therefore, should be warned against excessive alcohol intake while receiving JENTADUETO [see Warnings and Precautions (5.1)]. 5.9 Hypoxic States. Cardiovascular collapse (shock) from whatever cause (e.g., acute congestive heart failure, acute myocardial infarction, and other conditions characterized by hypoxemia) have been associated with lactic acidosis and may also cause prerenal azotemia. When such events occur in patients on JENTADUETO therapy, the drug should be promptly discontinued [see Warnings and Precautions (5.1)]. 5.10 Macrovascular Outcomes. There have been no clinical studies establishing conclusive evidence of macrovascular risk reduction with linagliptin or metformin or any other antidiabetic drug.