TRAJENTA 5mg tablets medication leaflet

Trajenta 5 mg film-coated tablets

Each tablet contains 5 mg of linagliptin.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

8 mm diameter round, light red film-coated tablet debossed with “D5” on one side and the Boehringer

Ingelheim logo on the other.

Trajenta is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise toimprove glycaemic control as:monotherapy

* when metformin is inappropriate due to intolerance, or contraindicated due to renal impairment.combination therapy

* in combination with other medicinal products for the treatment of diabetes, including insulin,when these do not provide adequate glycaemic control (see sections 4.4, 4.5 and 5.1 foravailable data on different combinations).

The dose of linagliptin is 5 mg once daily. When linagliptin is added to metformin, the dose ofmetformin should be maintained, and linagliptin administered concomitantly.

When linagliptin is used in combination with a sulphonylurea or with insulin, a lower dose of thesulphonylurea or insulin, may be considered to reduce the risk of hypoglycaemia (see section 4.4)

For patients with renal impairment, no dose adjustment for linagliptin is required.

Pharmacokinetic studies suggest that no dose adjustment is required for patients with hepaticimpairment but clinical experience in such patients is lacking.

No dose adjustment is necessary based on age.

A clinical trial did not establish efficacy in paediatric patients 10 to 17 years of age (see section 4.8,5.1 and 5.2). Therefore, treatment of children and adolescents with linagliptin is not recommended.

Linagliptin has not been studied in paediatric patients under 10 years of age.

The tablets can be taken with or without a meal at any time of the day. If a dose is missed, it should betaken as soon as the patient remembers. A double dose should not be taken on the same day.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Linagliptin should not be used in patients with type 1 diabetes or for the treatment of diabeticketoacidosis.

Linagliptin alone showed a comparable incidence of hypoglycaemia to placebo.

In clinical trials of linagliptin as part of combination therapy with medicinal products not known tocause hypoglycaemia (metformin), rates of hypoglycaemia reported with linagliptin were similar torates in patients taking placebo.

When linagliptin was added to a sulphonylurea (on a background of metformin), the incidence ofhypoglycaemia was increased over that of placebo (see section 4.8).

Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised whenlinagliptin is used in combination with a sulphonylurea and/or insulin. A dose reduction of thesulphonylurea or insulin may be considered (see section 4.2).

Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Acutepancreatitis has been observed in patients taking linagliptin. In a cardiovascular and renal safety study(CARMELINA) with median observation period of 2.2 years, adjudicated acute pancreatitis wasreported in 0.3% of patients treated with linagliptin and in 0.1% of patients treated with placebo.

Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis issuspected, Trajenta should be discontinued; if acute pancreatitis is confirmed, Trajenta should not berestarted. Caution should be exercised in patients with a history of pancreatitis.

Bullous pemphigoid

Bullous pemphigoid has been observed in patients taking linagliptin. In the CARMELINA study,bullous pemphigoid was reported in 0.2% of patients on treatment with linagliptin and in no patient onplacebo. If bullous pemphigoid is suspected, Trajenta should be discontinued.

In vitro assessment of interactions

Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme

CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes.

Linagliptin is a P-glycoprotein substrate, and inhibits P-glycoprotein mediated transport of digoxinwith low potency. Based on these results and in vivo interaction studies, linagliptin is consideredunlikely to cause interactions with other P-gp substrates.

In vivo assessment of interactions

Effects of other medicinal products on linagliptin

Clinical data described below suggest that the risk for clinically meaningful interactions byco-administered medicinal products is low.

Rifampicin: multiple co-administration of 5 mg linagliptin with rifampicin, a potent inductor of

P-glycoprotein and CYP3A4, resulted in a 39.6% and 43.8% decreased linagliptin steady-state AUCand Cmax, respectively, and about 30% decreased DPP-4 inhibition at trough. Thus, full efficacy oflinagliptin in combination with strong P-gp inducers might not be achieved, particularly if these areadministered long-term. Co-administration with other potent inducers of P-glycoprotein and CYP3A4,such as carbamazepine, phenobarbital and phenytoin has not been studied.

Ritonavir: co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral dosesof ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, increased the AUC and Cmax oflinagliptin approximately twofold and threefold, respectively. The unbound concentrations, which areusually less than 1% at the therapeutic dose of linagliptin, were increased 4-5-fold after co-administration with ritonavir. Simulations of steady-state plasma concentrations of linagliptin with andwithout ritonavir indicated that the increase in exposure will be not associated with an increasedaccumulation. These changes in linagliptin pharmacokinetics were not considered to be clinicallyrelevant. Therefore, clinically relevant interactions would not be expected with other

P-glycoprotein/CYP3A4 inhibitors.

Metformin: co-administration of multiple three times daily doses of 850 mg metformin with 10 mglinagliptin once daily did not clinical meaningfully alter the pharmacokinetics of linagliptin in healthyvolunteers.

Sulphonylureas: the steady-state pharmacokinetics of 5 mg linagliptin was not changed byconcomitant administration of a single 1.75 mg dose glibenclamide (glyburide).

Effects of linagliptin on other medicinal products

In clinical studies, as described below, linagliptin had no clinically relevant effect on thepharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin or oral contraceptivesproviding in vivo evidence of a low propensity for causing medicinal product interactions withsubstrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cationic transporter (OCT).

Metformin: co-administration of multiple daily doses of 10 mg linagliptin with 850 mg metformin, an

OCT substrate, had no relevant effect on the pharmacokinetics of metformin in healthy volunteers.

Therefore, linagliptin is not an inhibitor of OCT-mediated transport.

Sulphonylureas: co-administration of multiple oral doses of 5 mg linagliptin and a single oral dose of1.75 mg glibenclamide (glyburide) resulted in clinically not relevant reduction of 14% of both AUCand Cmax of glibenclamide. Because glibenclamide is primarily metabolised by CYP2C9, these dataalso support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically meaningfulinteractions would not be expected with other sulphonylureas (e.g., glipizide, tolbutamide, andglimepiride) which, like glibenclamide, are primarily eliminated by CYP2C9.

Digoxin: co-administration of multiple daily doses of 5 mg linagliptin with multiple doses of 0.25 mgdigoxin had no effect on the pharmacokinetics of digoxin in healthy volunteers. Therefore, linagliptinis not an inhibitor of P-glycoprotein-mediated transport in vivo.

Warfarin: multiple daily doses of 5 mg linagliptin did not alter the pharmacokinetics of S(-) or R(+)warfarin, a CYP2C9 substrate, administered in a single dose.

Simvastatin: multiple daily doses of linagliptin had a minimal effect on the steady-statepharmacokinetics of simvastatin, a sensitive CYP3A4 substrate, in healthy volunteers. Followingadministration of a supratherapeutic dose of 10 mg linagliptin concomitantly with 40 mg ofsimvastatin daily for 6 days, the plasma AUC of simvastatin was increased by 34%, and the plasma

Cmax by 10%.

Oral contraceptives: co-administration with 5 mg linagliptin did not alter the steady-statepharmacokinetics of levonorgestrel or ethinylestradiol.

The use of linagliptin has not been studied in pregnant women. Animal studies do not indicate director indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionarymeasure, it is preferable to avoid the use of linagliptin during pregnancy.

Available pharmacokinetic data in animals have shown excretion of linagliptin/metabolites in milk. Arisk to the breast-fed child cannot be excluded. A decision must be made whether to discontinuebreast-feeding or to discontinue/abstain from linagliptin therapy taking into account the benefit ofbreast-feeding for the child and the benefit of therapy for the woman.

No studies on the effect on human fertility have been conducted for linagliptin. Animal studies do notindicate direct or indirect harmful effects with respect to fertility (see section 5.3).

Linagliptin has no or negligible influence on the ability to drive and use machines. However patientsshould be alerted to the risk of hypoglycaemia especially when combined with sulphonylurea and/orinsulin.

In the pooled analysis of the placebo-controlled trials, the overall incidence of adverse events inpatients treated with placebo was similar to linagliptin 5 mg (63.4% versus 59.1%).

Discontinuation of therapy due to adverse events was higher in patients who received placebo ascompared to linagliptin 5 mg (4.3% versus 3.4%).

The most frequently reported adverse reaction was “hypoglycaemia” observed under the triplecombination, linagliptin plus metformin plus sulphonylurea 14.8% versus 7.6% in placebo.

In the placebo-controlled studies 4.9% of patients experienced “hypoglycaemia” as an adversereaction under linagliptin. Of these, 4.0% were mild and 0.9% were moderate and 0.1% wereclassified as severe in intensity. Pancreatitis was reported more often in patients randomized tolinagliptin (7 events in 6 580 patients receiving linagliptin versus 2 events in 4 383 patients receivingplacebo).

Due to the impact of the background therapy on adverse reactions (e.g. on hypoglycaemias), adversereactions were analysed based on the respective treatment regimens (monotherapy, add-on tometformin, add-on to meformin plus sulphonylurea, and add-on to insulin).

The placebo-controlled studies included studies where linagliptin was given as

- monotherapy with short-term duration of up to 4 weeks

- monotherapy with ≥ 12 week duration

- add-on to metformin

- add-on to metformin + sulphonylurea

- add on to metformin and empagliflozin

- add-on to insulin with or without metformin

Adverse reactions classified by system organ class and MedDRA preferred terms reported in patientswho received 5 mg linagliptin in double-blind studies as monotherapy or as add-on therapy arepresented in the table below (see table 1).

The adverse reactions are listed by absolute frequency. Frequencies are defined as very common(≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to< 1/1 000), very rare (< 1/10 000) or not known (cannot be estimated from the available data).

Table 1 Adverse reactions reported in patients who received linagliptin 5 mg daily asmonotherapy or as add-on therapies in clinical trial and from post-marketing experience

System organ class

Frequency of adverse reaction

Adverse reaction

Nasopharyngitis uncommon

Hypersensitivityuncommon(e.g. bronchial hyperreactivity)

Hypoglycaemia1 very common

Cough uncommon

Pancreatitis rare #

Constipation2 uncommon

Angioedema* rare

Urticaria* rare

Rash* uncommon

Bullous pemphigoid rare #

Amylase increased uncommon

Lipase increased** common

* Based on post-marketing experience

** Based on lipase elevations > 3 × ULN observed in clinical trials# Based on Linagliptin cardiovascular and renal safety study (CARMELINA), see also below1 Adverse reaction observed in combination with metformin plus sulphonylurea2 Adverse reaction observed in combination with insulin

Linagliptin cardiovascular and renal safety study (CARMELINA)

The CARMELINA study evaluated the cardiovascular and renal safety of linagliptin versus placebo inpatients with type 2 diabetes and with increased CV risk evidenced by a history of establishedmacrovascular or renal disease (see section 5.1). The study included 3 494 patients treated withlinagliptin (5 mg) and 3 485 patients treated with placebo. Both treatments were added to standard ofcare targeting regional standards for HbA1c and CV risk factors. The overall incidence of adverseevents and serious adverse events in patients receiving linagliptin was similar to that in patientsreceiving placebo. Safety data from this study was in line with previous known safety profile oflinagliptin.

In the treated population, severe hypoglycaemic events (requiring assistance) were reported in 3.0% ofpatients on linagliptin and in 3.1% on placebo. Among patients who were using sulfonylurea atbaseline, the incidence of severe hypoglycaemia was 2.0% in linagliptin-treated patients and 1.7% inplacebo treated patients. Among patients who were using insulin at baseline, the incidence of severehypoglycaemia was 4.4% in linagliptin-treated patients and 4.9% in placebo treated patients.

In the overall study observation period adjudicated acute pancreatitis was reported in 0.3% of patientstreated with linagliptin and in 0.1% of patients treated with placebo.

In the CARMELINA study, bullous pemphigoid was reported in 0.2% of patients treated withlinagliptin and in no patient treated with placebo.

Overall, in clinical trials in paediatric patients with type 2 diabetes mellitus aged 10 to 17 years, thesafety profile of linagliptin was similar to that observed in the adult population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

During controlled clinical trials in healthy subjects, single doses of up to 600 mg linagliptin(equivalent to 120 times the recommended dose) were generally well tolerated. There is no experiencewith doses above 600 mg in humans.

In the event of an overdose, it is reasonable to employ the usual supportive measures, e.g., removeunabsorbed material from the gastrointestinal tract, employ clinical monitoring and institute clinicalmeasures if required.

Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors,

ATC code: A10BH05

Linagliptin is an inhibitor of the enzyme DPP-4 (dipeptidyl peptidase 4, EC 3.4.14.5) an enzymewhich is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-likepeptide-1, glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by theenzyme DPP-4. Both incretin hormones are involved in the physiological regulation of glucosehomeostasis. Incretins are secreted at a low basal level throughout the day and levels rise immediatelyafter meal intake. GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic betacells in the presence of normal and elevated blood glucose levels. Furthermore GLP-1 also reducesglucagon secretion from pancreatic alpha cells, resulting in a reduction in hepatic glucose output.

Linagliptin binds very effectively to DPP-4 in a reversible manner and thus leads to a sustainedincrease and a prolongation of active incretin levels. Linagliptin glucose-dependently increases insulinsecretion and lowers glucagon secretion thus resulting in an overall improvement in the glucosehomeostasis. Linagliptin binds selectively to DPP-4 and exhibits a > 10 000 fold selectivity versus

DPP-8 or DPP-9 activity in vitro.

Clinical efficacy and safety8 phase III randomised controlled trials involving 5 239 patients with type 2 diabetes, of which 3 319were treated with linagliptin were conducted to evaluate efficacy and safety. These studies had929 patients of 65 years and over who were on linagliptin. There were also 1 238 patients with mildrenal impairment, and 143 patients with moderate renal impairment on linagliptin. Linagliptin oncedaily produced clinically significant improvements in glycaemic control, with no clinically relevantchange in body weight. The reductions in glycosylated haemoglobin A1c (HbA1c) were similar acrossdifferent subgroups including gender, age, renal impairment and body mass index (BMI). Higherbaseline HbA1c was associated with a greater reduction in HbA1c. There was a significant difference inreduction in HbA1c between Asian patients (0.8%) and White patients (0.5%) in the pooled studies.

Linagliptin as monotherapy in patients ineligible for metformin

The efficacy and safety of linagliptin monotherapy was evaluated in a double-blind placebo-controlledstudy of 24 weeks duration. Treatment with once daily linagliptin at 5 mg provided a significantimprovement in HbA1c (-0.69% change compared to placebo), in patients with baseline HbA1c ofapproximately 8%. Linagliptin also showed significant improvements in fasting plasma glucose(FPG), and 2-hour post-prandial glucose (PPG) compared to placebo. The observed incidence ofhypoglycaemia in patients treated with linagliptin was similar to placebo.

The efficacy and safety of linagliptin monotherapy was also evaluated in patients for whom metformintherapy is inappropriate, due to intolerability or contraindicated due to renal impairment, in a double-blind placebo-controlled study of 18 weeks duration. Linagliptin provided significant improvements in

HbA1c, (-0.57% change compared to placebo), from a mean baseline HbA1c of 8.09%. Linagliptin alsoshowed significant improvements in fasting plasma glucose (FPG) compared to placebo. The observedincidence of hypoglycaemia in patients treated with linagliptin was similar to placebo.

Linagliptin as add-on to metformin therapy

The efficacy and safety of linagliptin in combination with metformin was evaluated in a double-blindplacebo-controlled study of 24 weeks duration. Linagliptin provided significant improvements in

HbA1c, (-0.64% change compared to placebo), from a mean baseline HbA1c of 8%. Linagliptin alsoshowed significant improvements in fasting plasma glucose (FPG), and 2-hour post-prandial glucose(PPG) compared to placebo. The observed incidence of hypoglycaemia in patients treated withlinagliptin was similar to placebo.

Linagliptin as add-on to a combination of metformin and sulphonylurea therapy

A placebo-controlled study of 24 weeks in duration was conducted to evaluate the efficacy and safetyof linagliptin 5 mg to placebo, in patients not sufficiently treated with a combination with metforminand a sulphonylurea. Linagliptin provided significant improvements in HbA1c (-0.62% changecompared to placebo), from a mean baseline HbA1c of 8.14%. Linagliptin also showed significantimprovements in patients fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG),compared to placebo.

Linagliptin as add-on to a combination of metformin and empagliflozin therapy

In patients inadequately controlled with metformin and empagliflozin (10 mg (n = 247) or 25 mg(n = 217)), 24-weeks treatment with add-on therapy of linagliptin 5 mg provided adjusted mean HbA1creductions from baseline by -0.53% (significant difference to add-on placebo -0.32% (95%

CI -0.52, -0.13) and -0.58% (significant difference to add-on placebo -0.47% (95% CI -0.66; -0.28),respectively. A statistically significant greater proportion of patients with a baseline HbA1c ≥ 7.0% andtreated with linagliptin 5 mg achieved a target HbA1c of < 7% compared to placebo.

Linagliptin as add-on to insulin therapy

The efficacy and safety of the addition of linagliptin 5 mg to insulin alone or in combination withmetformin and/or pioglitazone has been evaluated in a double-blind placebo-controlled study of24 weeks duration. Linagliptin provided significant improvements in HbA1c (-0.65% compared toplacebo) from a mean baseline HbA1c of 8.3%. Linagliptin also provided significant improvements infasting plasma glucose (FPG), and a greater proportion of patients achieved a target HbA1c of < 7.0%,compared to placebo. This was achieved with a stable insulin dose (40.1 IU). Body weight did notdiffer significantly between the groups. Effects on plasma lipids were negligible. The observedincidence of hypoglycaemia in patients treated with linagliptin was similar to placebo (22.2%linagliptin; 21.2% placebo).

Linagliptin 24 month data, as add-on to metformin in comparison with glimepiride

In a study comparing the efficacy and safety of the addition of linagliptin 5 mg or glimepiride (meandose 3 mg) in patients with inadequate glycaemic control on metformin monotherapy, mean reductionsin HbA1c were -0.16% with linagliptin (mean baseline HbA1c 7.69%) and -0.36% with glimepiride(mean baseline HbA1c 7.69%.) with a mean treatment difference of 0.20% (97.5% CI: 0.09, 0.299).

The incidence of hypoglycaemia in the linagliptin group (7.5%) was significantly lower than that inthe glimepiride group (36.1%). Patients treated with linagliptin exhibited a significant mean decreasefrom baseline in body weight compared to a significant weight gain in patients administeredglimepiride (-1.39 vs +1.29 kg).

Linagliptin as add-on therapy in patients with severe renal impairment, 12 week placebo-controlleddata (stable background) and 40 week placebo-controlled extension (adjustable background)

The efficacy and safety of linagliptin was also evaluated in type 2 diabetes patients with severe renalimpairment in a double-blind study versus placebo for 12 weeks duration, during which backgroundglycaemic therapies were kept stable. Most patients (80.5%) received insulin as background therapy,alone or in combination with other oral anti-diabetics such as sulphonylurea, glinide and pioglitazone.

There was a further follow up 40 week treatment period during which dose adjustments in antidiabetesbackground therapies were allowed.

Linagliptin provided significant improvements in HbA1c (-0.59 % change compared to placebo after12 weeks), from a mean baseline HbA1c of 8.2%. The observed difference in HbA1c over placebowas -0.72% after 52 weeks.

Body weight did not differ significantly between the groups. The observed incidence ofhypoglycaemia in patients treated with linagliptin was higher than placebo, due to an increase inasymptomatic hypoglycaemic events. There was no difference between groups in severehypoglycaemic events.

Linagliptin as add-on therapy in elderly (age ≥ 70 years) with type 2 diabetes

The efficacy and safety of linagliptin in elderly (age ≥ 70 years) with type 2 diabetes was evaluated ina double-blind study of 24 weeks duration. Patients received metformin and/or sulphonylurea and/orinsulin as background therapy. Doses of background antidiabetic medicinal products were kept stableduring the first 12 weeks, after which adjustments were permitted. Linagliptin provided significantimprovements in HbA1c (-0.64 % change compared to placebo after 24 weeks), from a mean baseline

HbA1c of 7.8%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG)compared to placebo. Body weight did not differ significantly between the groups.

Linagliptin cardiovascular and renal safety study (CARMELINA)

CARMELINA was a randomized study in 6 979 patients with type 2 diabetes with increased CV riskevidenced by a history of established macrovascular or renal disease who were treated with linagliptin5 mg (3 494) or placebo (3 485) added to standard of care targeting regional standards for HbA1c, CVrisk factors and renal disease. The study population included 1 211 (17.4%) patients ≥ 75 years of ageand 4 348 (62.3%) patients with renal impairment. Approximately 19% of the population had eGFR≥ 45 to < 60 mL/min/1.73 m2, 28% of the population had eGFR ≥ 30 to < 45 mL/min/1.73 m2 and15% had eGFR < 30 mL/min/1.73 m2. The mean HbA1c at baseline was 8.0%.

The study was designed to demonstrate non-inferiority for the primary cardiovascular endpoint whichwas a composite of the first occurrence of cardiovascular death or a non-fatal myocardial infarction(MI) or a non-fatal stroke (3P-MACE). The renal composite endpoint was defined as renal death orsustained end stage renal disease or sustained decrease of 40% or more in eGFR.

After a median follow up of 2.2 years, linagliptin, when added to usual care, did not increase the riskof major adverse cardiovascular events or renal outcome events. There was no increased risk inhospitalization for heart failure which was an additional adjudicated endpoint observed compared tousual care without linagliptin in patients with type 2 diabetes (see table 2).

Table 2 Cardiovascular and renal outcomes by treatment group in the CARMELINA study

Linagliptin 5 mg Placebo Hazard Ratio

Number of Incidence Number of Incidence (95% CI)

Subjects Rate per Subjects Rate per(%) 1 000 PY* (%) 1 000 PY*

Number of patients 3 494 3 485

Primary CV 434 (12.4) 57.7 420 (12.1) 56.3 1.02 (0.89, 1.17)**composite(Cardiovasculardeath, non-fatal MI,non-fatal stroke)

Secondary renal 327 (9.4) 48.9 306 (8.8) 46.6 1.04 (0.89, 1.22)composite (renaldeath, ESRD, 40%sustained decrease ineGFR)

All-cause mortality 367 (10.5) 46.9 373 (10.7) 48.0 0.98 (0.84, 1.13)

CV death 255 (7.3) 32.6 264 (7.6) 34 0.96 (0.81, 1.14)

Hospitalization for 209 (6.0) 27.7 226 (6.5) 30.4 0.90 (0.74, 1.08)heart failure

* PY = patient years

** Test on non-inferiority to demonstrate that the upper bound of the 95% CI for the hazard ratio is less than 1.3

In analyses for albuminuria progression (change from normoalbuminuria to micro- ormacroalbuminuria, or from microalbuminuria to macroalbuminuria) the estimated hazard ratio was0.86 (95% CI 0.78, 0.95) for linagliptin versus placebo.

Linagliptin cardiovascular safety study (CAROLINA)

CAROLINA was a randomized study in 6 033 patients with early type 2 diabetes and increased CVrisk or established complications who were treated with linagliptin 5 mg (3 023) or glimepiride 1-4 mg(3 010) added to standard of care (including background therapy with metformin in 83% of patients)targeting regional standards for HbA1c and CV risk factors. The mean age for study population was64 years and included 2 030 (34%) patients ≥ 70 years of age. The study population included 2 089(35%) patients with cardiovascular disease and 1 130 (19%) patients with renal impairment with aneGFR < 60 mL/min/1.73 m2 at baseline. The mean HbA1c at baseline was 7.15%.

The study was designed to demonstrate non-inferiority for the primary cardiovascular endpoint whichwas a composite of the first occurrence of cardiovascular death or a non-fatal myocardial infarction(MI) or a non-fatal stroke (3P-MACE).

After a median follow up of 6.25 years, linagliptin did not increase the risk of major adversecardiovascular events (see table 3) as compared to glimepiride. Results were consistent for patientstreated with or without metformin.

Table 3 Major adverse cardiovascular events (MACE) and mortality by treatment group in the

CAROLINA study

Linagliptin 5 mg Glimepiride (1-4 mg) Hazard Ratio

Number of Incidence Number of Incidence (95% CI)

Subjects Rate per Subjects Rate per(%) 1 000 PY* (%) 1 000 PY*

Number of patients 3 023 3 010

Primary CV 356 (11.8) 20.7 362 (12.0) 21.2 0.98 (0.84, 1.14)**composite(Cardiovasculardeath, non-fatal MI,non-fatal stroke)

All-cause mortality 308 (10.2) 16.8 336 (11.2) 18.4 0.91 (0.78, 1.06)

CV death 169 (5.6) 9.2 168 (5.6) 9.2 1.00 (0.81, 1.24)

Hospitalization for 112 (3.7) 6.4 92 (3.1) 5.3 1.21 (0.92, 1.59)heart failure (HHF)

* PY = patient years

** Test on non-inferiority to demonstrate that the upper bound of the 95% CI for the hazard ratio is less than 1.3

For the entire treatment period (median time on treatment 5.9 years) the rate of patients with moderateor severe hypoglycaemia was 6.5% on linagliptin versus 30.9% on glimepiride, severe hypoglycaemiaoccurred in 0.3% of patients on linagliptin versus 2.2% on glimepiride.

The clinical efficacy and safety of empagliflozin 10 mg with potential dose-increase to 25 mg orlinagliptin 5 mg once daily has been studied in children and adolescents from 10 to 17 years of agewith T2DM in a double-blind, randomised, placebo-controlled, parallel group study (DINAMO) over26 weeks, with a double-blind active treatment safety extension period up to 52 weeks.

At baseline, the mean HbA1c was 8.03%. Treatment with linagliptin 5 mg did not provide significantimprovement in HbA1c. The treatment difference of adjusted mean change in HbA1c after 26 weeksbetween linagliptin and placebo was -0.34% (95% CI -0.99, 0.30; p = 0.2935). The adjusted meanchange in HbA1c from baseline was 0.33% in patients treated with linagliptin and 0.68% in patientstreated with placebo (see section 4.2).

The pharmacokinetics of linagliptin has been extensively characterised in healthy subjects and patientswith type 2 diabetes. After oral administration of a 5 mg dose to healthy volunteers or patients,linagliptin was rapidly absorbed, with peak plasma concentrations (median Tmax) occurring 1.5 hourspost-dose.

Plasma concentrations of linagliptin decline in a triphasic manner with a long terminal half-life(terminal half-life for linagliptin more than 100 hours), that is mostly related to the saturable, tightbinding of linagliptin to DPP-4 and does not contribute to the accumulation of the medicinal product.

The effective half-life for accumulation of linagliptin, as determined from oral administration ofmultiple doses of 5 mg linagliptin, is approximately 12 hours. After once daily dosing of 5 mglinagliptin, steady-state plasma concentrations are reached by the third dose. Plasma AUC oflinagliptin increased approximately 33% following 5 mg doses at steady-state compared to the firstdose. The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small(12.6% and 28.5%, respectively). Due to the concentration dependent binding of linagliptin to DPP-4,the pharmacokinetics of linagliptin based on total exposure is not linear; indeed total plasma AUC oflinagliptin increased in a less than dose-proportional manner while unbound AUC increases in aroughly dose-proportional manner. The pharmacokinetics of linagliptin was generally similar inhealthy subjects and in patients with type 2 diabetes.

The absolute bioavailability of linagliptin is approximately 30%. Co-administration of a high-fat mealwith linagliptin prolonged the time to reach Cmax by 2 hours and lowered Cmax by 15% but no influenceon AUC0-72h was observed. No clinically relevant effect of Cmax and Tmax changes is expected;therefore linagliptin may be administered with or without food.

As a result of tissue binding, the mean apparent volume of distribution at steady-state following asingle 5 mg intravenous dose of linagliptin to healthy subjects is approximately 1 110 litres, indicatingthat linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin isconcentration-dependent, decreasing from about 99% at 1 nmol/L to 75-89% at ≥ 30 nmol/L,reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At highconcentrations, where DPP-4 is fully saturated, 70-80% of linagliptin was bound to other plasmaproteins than DPP-4, hence 30-20% were unbound in plasma.

Following a [14C] linagliptin oral 10 mg dose, approximately 5% of the radioactivity was excreted inurine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite witha relative exposure of 13.3% of linagliptin at steady-state was detected which was found to bepharmacologically inactive and thus does not contribute to the plasma DPP-4 inhibitory activity oflinagliptin.

Following administration of an oral [14C] linagliptin dose to healthy subjects, approximately 85% ofthe administered radioactivity was eliminated in faeces (80%) or urine (5%) within 4 days of dosing.

Renal clearance at steady-state was approximately 70 mL/min.

A multiple-dose, open-label study was conducted to evaluate the pharmacokinetics of linagliptin (5 mgdose) in patients with varying degrees of chronic renal insufficiency compared to normal healthycontrol subjects. The study included patients with renal insufficiency classified on the basis ofcreatinine clearance as mild (50 to < 80 mL/min), moderate (30 to < 50 mL/min), and severe(< 30 mL/min), as well as patients with ESRD on hemodialysis. In addition patients with T2DM andsevere renal impairment (< 30 mL/min) were compared to T2DM patients with normal renal function.

Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimatedfrom serum creatinine based on the Cockcroft-Gault formula. CrCl = (140 - age) × weight/72 × serumcreatinine [× 0.85 for females], where age is in years, weight in kg, and serum creatinine is in mg/dl.

Under steady-state conditions, linagliptin exposure in patients with mild renal impairment wascomparable to healthy subjects. In moderate renal impairment, a moderate increase in exposure ofabout 1.7 fold was observed compared with control. Exposure in T2DM patients with severe RI wasincreased by about 1.4 fold compared to T2DM patients with normal renal function. Steady-statepredictions for AUC of linagliptin in patients with ESRD indicated comparable exposure to that ofpatients with moderate or severe renal impairment. In addition, linagliptin is not expected to beeliminated to a therapeutically significant degree by hemodialysis or peritoneal dialysis. Therefore, nodosage adjustment of linagliptin is necessary in patients with any degree of renal insufficiency.

In non-diabetic patients with mild moderate and severe hepatic insufficiency (according to the

Child-Pugh classification), mean AUC and Cmax of linagliptin were similar to healthy matched controlsfollowing administration of multiple 5 mg doses of linagliptin. No dosage adjustment for linagliptin isproposed for diabetic patients with mild, moderate or severe hepatic impairment.

Body Mass Index (BMI)

No dosage adjustment is necessary based on BMI. BMI had no clinically relevant effect on thepharmacokinetics of linagliptin based on a population pharmacokinetic analysis of phase I and phase IIdata. The clinical trials before marketing authorisation have been performed up to a BMI equal to40 kg/m2.

No dosage adjustment is necessary based on gender. Gender had no clinically relevant effect on thepharmacokinetics of linagliptin based on a population pharmacokinetic analysis of phase I and phase IIdata.

No dosage adjustment is required based on age up to 80 years, as age did not have a clinically relevantimpact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis ofphase I and phase II data. Older subjects (65 to 80, oldest patient was 78 years) had comparableplasma concentrations of linagliptin compared to younger subjects.

A paediatric phase II study examined the pharmacokinetics and pharmacodynamics of 1 mg and 5 mglinagliptin in children and adolescents ≥ 10 to < 18 years of age with type 2 diabetes mellitus. Theobserved pharmacokinetic and pharmacodynamic responses were consistent with those found in adultsubjects. Linagliptin 5 mg showed superiority over 1 mg with regard to trough DPP-4 inhibition (72%vs 32%, p = 0.0050) and a numerically larger reduction with regard to adjusted mean change frombaseline in HbA1c (-0.63% vs -0.48%, n.s.). Due to the limited nature of the data set the results shouldbe interpreted cautiously.

A paediatric phase III study examined pharmacokinetics and pharmacodynamics (HbA1c change frombaseline) of 5 mg linagliptin in children and adolescents 10 to 17 years of age with type 2 diabetesmellitus. The observed exposure-response relationship was generally comparable between paediatricand adult patients, however, with a smaller drug effect estimated in children. Oral administration oflinagliptin resulted in exposure within the range observed in adult patients. The observed geometricmean trough concentrations and geometric mean concentrations at 1.5 hours post-administration(representing a concentration around tmax) at steady state were 4.30 nmol/L and 12.6 nmol/L,respectively. Corresponding plasma concentrations in adult patients were 6.04 nmol/L and15.1 nmol/L.

No dosage adjustment is necessary based on race. Race had no obvious effect on the plasmaconcentrations of linagliptin based on a composite analysis of available pharmacokinetic data,including patients of Caucasian, Hispanic, African, and Asian origin. In addition the pharmacokineticcharacteristics of linagliptin were found to be similar in dedicated phase I studies in Japanese, Chineseand Caucasian healthy volunteers.

Liver, kidneys and gastrointestinal tract are the principal target organs of toxicity in mice and rats atrepeat doses of linagliptin of more than 300 times the human exposure.

In rats effects on reproductive organs, thyroid and the lymphoid organs were seen at more than1 500 times human exposure. Strong pseudo-allergic reactions were observed in dogs at mediumdoses, secondarily causing cardiovascular changes, which were considered dog-specific. Liver,kidneys, stomach, reproductive organs, thymus, spleen, and lymph nodes were target organs oftoxicity in Cynomolgus monkeys at more than 450 times human exposure. At more than 100 timeshuman exposure, irritation of the stomach was the major finding in these monkeys.

Linagliptin and its main metabolite did not show a genotoxic potential.

Oral 2 year carcinogenicity studies in rats and mice revealed no evidence of carcinogenicity in rats ormale mice. A significantly higher incidence of malignant lymphomas only in female mice at thehighest dose (> 200 times human exposure) is not considered relevant for humans (explanation: non-treatment related but due to highly variable background incidence). Based on these studies there is noconcern for carcinogenicity in humans.

The NOAEL for fertility, early embryonic development and teratogenicity in rats was set at> 900 times the human exposure. The NOAEL for maternal-, embryo-fetal-, and offspring toxicity inrats was 49 times human exposure. No teratogenic effects were observed in rabbits at > 1 000 timeshuman exposure. A NOAEL of 78 times human exposure was derived for embryo-fetal toxicity inrabbits, and for maternal toxicity the NOAEL was 2.1 times human exposure. Therefore, it isconsidered unlikely that linagliptin affects reproduction at therapeutic exposures in humans.

Mannitol

Pregelatinised starch (maize)

Maize starch

Copovidone

Magnesium stearate

Hypromellose

Titanium dioxide (E171)

Talc

Macrogol (6000)

Iron oxide red (E172)

Not applicable.

3 years

This medicinal product does not require any special storage conditions.

Perforated alu/alu unit dose blisters in cartons containing 10 × 1, 14 × 1, 28 × 1, 30 × 1, 56 × 1, 60 × 1,84 × 1, 90 × 1, 98 × 1, 100 × 1 and 120 × 1 film-coated tablets.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

Boehringer Ingelheim International GmbH

Binger Str. 17355216 Ingelheim am Rhein

Germany

EU/1/11/707/001 (10 × 1 tablets)

EU/1/11/707/002 (14 × 1 tablets)

EU/1/11/707/003 (28 × 1 tablets)

EU/1/11/707/004 (30 × 1 tablets)

EU/1/11/707/005 (56 × 1 tablets)

EU/1/11/707/006 (60 × 1 tablets)

EU/1/11/707/007 (84 × 1 tablets)

EU/1/11/707/008 (90 × 1 tablets)

EU/1/11/707/009 (98 × 1 tablets)

EU/1/11/707/010 (100 × 1 tablets)

EU/1/11/707/011 (120 × 1 tablets)

Date of first authorisation: 24 August 2011

Date of latest renewal: 22 March 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.