JENTADUETO 2.5mg / 850mg tablets medication leaflet

Jentadueto 2.5 mg/850 mg film-coated tablets

Jentadueto 2.5 mg/1 000 mg film-coated tablets

Jentadueto 2.5 mg/850 mg film-coated tablets

Each tablet contains 2.5 mg of linagliptin and 850 mg of metformin hydrochloride.

Jentadueto 2.5 mg/1 000 mg film-coated tablets

Each tablet contains 2.5 mg of linagliptin and 1 000 mg of metformin hydrochloride.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Jentadueto 2.5 mg/850 mg film-coated tablets

Oval, biconvex, light orange, film-coated tablet of 19.2 mm × 9.4 mm debossed with “D2/850” on oneside and the company logo on the other.

Jentadueto 2.5 mg/1 000 mg film-coated tablets

Oval, biconvex, light pink, film-coated tablet of 21.1 mm × 9.7 mm debossed with “D2/1000” on oneside and the company logo on the other.

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

* in patients inadequately controlled on their maximally tolerated dose of metformin alone

* in combination with other medicinal products for the treatment of diabetes, including insulin, inpatients inadequately controlled with metformin and these medicinal products

* in patients already being treated with the combination of linagliptin and metformin as separatetablets.

(see sections 4.4, 4.5 and 5.1 for available data on different combinations).

Adults with normal renal function (GFR ≥ 90 mL/min)

The dose of antihyperglycaemic therapy with Jentadueto should be individualised on the basis of thepatient’s current regimen, effectiveness, and tolerability, while not exceeding the maximumrecommended daily dose of 5 mg linagliptin plus 2 000 mg of metformin hydrochloride.

Patients inadequately controlled on maximal tolerated dose of metformin monotherapy

For patients not adequately controlled on metformin alone, the usual starting dose of Jentaduetoshould provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose) plus the dose ofmetformin already being taken.

Patients switching from co-administration of linagliptin and metformin

For patients switching from co-administration of linagliptin and metformin, Jentadueto should beinitiated at the dose of linagliptin and metformin already being taken.

Patients inadequately controlled on dual combination therapy with the maximal tolerated dose ofmetformin and a sulphonylurea

The dose of Jentadueto should provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose)and a dose of metformin similar to the dose already being taken. When linagliptin plus metforminhydrochloride is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may berequired to reduce the risk of hypoglycaemia (see section 4.4).

Patients inadequately controlled on dual combination therapy with insulin and the maximal tolerateddose of metformin

The dose of Jentadueto should provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose)and a dose of metformin similar to the dose already being taken. When linagliptin plus metforminhydrochloride is used in combination with insulin, a lower dose of insulin may be required to reducethe risk of hypoglycaemia (see section 4.4).

For the different doses of metformin, Jentadueto is available in strengths of 2.5 mg linagliptin plus850 mg metformin hydrochloride and 2.5 mg linagliptin plus 1 000 mg metformin hydrochloride.

As metformin is excreted by the kidney, Jentadueto should be used with caution as age increases.

Monitoring of renal function is necessary to aid in prevention of metformin-associated lactic acidosis,particularly in the elderly (see sections 4.3 and 4.4).

A GFR should be assessed before initiation of treatment with metformin containing products and atleast annually thereafter. In patients at an increased risk of further progression of renal impairment andin the elderly, renal function should be assessed more frequently, e.g. every 3-6 months.

Factors that may increase the risk of lactic acidosis (see 4.4) should be reviewed before consideringinitiation of metformin in patients with GFR< 60 mL/min.

If no adequate strength of Jentadueto is available, individual monocomponents should be used insteadof the fixed dose combination.

Table 1: Posology for renally impaired patients

GFR mL/min Metformin Linagliptin60-89 Maximum daily dose is 3 000 mg. No dose adjustment

Dose reduction may be considered inrelation to declining renal function.

45-59 Maximum daily dose is 2 000 mg No dose adjustment

The starting dose is at most half of themaximum dose.

30-44 Maximum daily dose is 1 000 mg. No dose adjustment

The starting dose is at most half of themaximum dose.

< 30 Metformin is contraindicated No dose adjustment

Jentadueto is not recommended in patients with hepatic impairment due to the active substancemetformin (see sections 4.3 and 5.2). Clinical experience with Jentadueto in patients with hepaticimpairment is lacking.

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.

Jentadueto should be taken twice daily with meals to reduce the gastrointestinal adverse reactionsassociated with metformin.

All patients should continue their diet with an adequate distribution of carbohydrate intake during theday. Overweight patients should continue their energy-restricted diet.

If a dose is missed, it should be taken as soon as the patient remembers. However, a double doseshould not be taken at the same time. In that case, the missed dose should be skipped.

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

* Any type of acute metabolic acidosis (such as lactic acidosis, diabetic ketoacidosis)

* Diabetic pre-coma.

* Severe renal failure (GFR < 30 mL/min).

* Acute conditions with the potential to alter renal function such as: dehydration, severe infection,shock.

* Disease which may cause tissue hypoxia (especially acute disease, or worsening of chronicdisease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction,shock.

* Hepatic impairment, acute alcohol intoxication, alcoholism (see section 4.5).

Jentadueto should not be used in patients with type 1 diabetes.

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

Sulphonylureas and insulin are known to cause hypoglycaemia. Therefore, caution is advised when

Jentadueto is used in combination with a sulphonylurea and/or insulin. A dose reduction of thesulphonylurea or insulin may be considered (see section 4.2).

Hypoglycaemia is not identified as adverse reaction for linagliptin, metformin, or linagliptin plusmetformin. In clinical trials, the incidence rates of hypoglycemia were comparably low in patientstaking linagliptin in combination with metformin or metformin alone.

Lactic acidosis

Lactic acidosis, a very rare but serious metabolic complication, most often occurs at acute worseningof renal function or cardiorespiratory illness or sepsis. Metformin accumulation occurs at acuteworsening of renal function and increases the risk of lactic acidosis.

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin shouldbe temporarily discontinued and contact with a health care professional is recommended.

Medicinal products that can acutely impair renal function (such as antihypertensives, diuretics and

NSAIDs) should be initiated with caution in metformin-treated patients. Other risk factors for lacticacidosis are excessive alcohol intake, hepatic impairment, inadequately controlled diabetes, ketosis,prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinalproducts that may cause lactic acidosis (see sections 4.3 and 4.5).

Patients and/or care-givers should be informed of the risk of lactic acidosis. Lactic acidosis ischaracterised by acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followedby coma. In case of suspected symptoms, the patient should stop taking metformin and seekimmediate medical attention. Diagnostic laboratory findings are decreased blood pH (< 7.35),increased plasma lactate levels (> 5 mmol/L) and an increased anion gap and lactate/pyruvate ratio.

Patients with known or suspected mitochondrial diseases

In patients with known mitochondrial diseases such as Mitochondrial Encephalopathy with Lactic

Acidosis, and Stroke-like episodes (MELAS) syndrome and Maternal inherited diabetes and deafness(MIDD), metformin is not recommended due to the risk of lactic acidosis exacerbation and neurologiccomplications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake ofmetformin, treatment with metformin should be withdrawn immediately and prompt diagnosticevaluation should be performed.

Administration of iodinated contrast agent

Intravascular administration of iodinated contrast agents may lead to contrast induced nephropathy,resulting in metformin accumulation and an increased risk of lactic acidosis. Metformin should bediscontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hoursafter, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and4.5.

GFR should be assessed before treatment initiation and regularly thereafter, see section 4.2. Metforminis contraindicated in patients with GFR< 30 mL/min and should be temporarily discontinued in thepresence of conditions that alter renal function, see section 4.3).

Cardiac function

Patients with heart failure are more at risk of hypoxia and renal impairment. In patients with stablechronic heart failure, Jentadueto may be used with a regular monitoring of cardiac and renal function.

For patients with acute and unstable heart failure, Jentadueto is contraindicated (see section 4.3).

Metformin must be discontinued at the time of surgery under general, spinal or epidural anesthesia.

Therapy may be restarted no earlier than 48 hours following surgery or resumption of oral nutritionand provided that renal function has been re-evaluated and found to be stable.

Caution should be exercised when treating patients 80 years and older (see section 4.2).

Change in clinical status of patients with previously controlled type 2 diabetes

As Jentadueto contains metformin, a patient with previously well controlled type 2 diabetes on

Jentadueto who develops laboratory abnormalities or clinical illness (especially vague and poorlydefined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis.

Evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood pH,lactate, pyruvate, and metformin levels. If acidosis of either form occurs, Jentadueto must be stoppedimmediately and other appropriate corrective measures initiated.

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, Jentadueto should be discontinued; if acute pancreatitis is confirmed, Jentadueto should notbe restarted. 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, Jentadueto should be discontinued.

Vitamin B12

Metformin may reduce vitamin B12 levels. The risk of low vitamin B12 levels increases withincreasing metformin dose, treatment duration, and/or in patients with risk factors known to causevitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia orneuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring couldbe necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should becontinued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment forvitamin B12 deficiency provided in line with current clinical guidelines.

No interaction studies have been performed. However, such studies have been conducted with theindividual active substances, i.e. linagliptin and metformin. Co-administration of multiple doses oflinagliptin and metformin did not meaningfully alter the pharmacokinetics of either linagliptin ormetformin in healthy volunteers and patients.

Linagliptin

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 drug 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 bycoadministered medicinal products is low.

Co-administration of multiple three-times-daily doses of 850 mg metformin hydrochloride with 10 mglinagliptin once daily did not clinical meaningfully alter the pharmacokinetics of linagliptin in healthysubjects.

Sulphonylureas:

The steady-state pharmacokinetics of 5 mg linagliptin were not changed by concomitantadministration of a single 1.75 mg dose glibenclamide (glyburide).

Co-administration of a single 5 mg oral dose of linagliptin and multiple 200 mg oral doses of ritonavir,a potent inhibitor of P-glycoprotein and CYP3A4, increased the AUC and Cmax of linagliptinapproximately twofold and threefold, respectively. The unbound concentrations, which are usually lessthan 1% at the therapeutic dose of linagliptin, were increased 4-5-fold after co-administration withritonavir. Simulations of steady-state plasma concentrations of linagliptin with and without ritonavirindicated that the increase in exposure will not be associated with an increased accumulation. Thesechanges in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore,clinically relevant interactions would not be expected with other P-glycoprotein/CYP3A4 inhibitors.

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 AUC and Cmaxrespectively, and about 30% decreased DPP-4 inhibition at trough. Thus full efficacy of linagliptin incombination with strong P-gp inducers might not be achieved, particularly if these are administeredlong-term. Co-administration with other potent inducers of P-glycoprotein and CYP3A4, such ascarbamazepine, phenobarbital and phenytoin has not been studied.

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 interactions with substrates of CYP3A4,

CYP2C9, CYP2C8, P-glycoprotein, and organic cationic transporter (OCT).

Co-administration of multiple daily doses of 10 mg linagliptin with 850 mg metformin hydrochloride,an OCT substrate, had no relevant effect on the pharmacokinetics of metformin in healthy subjects.

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 of 1.75 mgglibenclamide (glyburide) resulted in clinically not relevant reduction of 14% of both AUC and Cmaxof glibenclamide. Because glibenclamide is primarily metabolised by CYP2C9, these data also supportthe conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically meaningful interactions would notbe expected with other sulphonylureas (e.g., glipizide, tolbutamide, and glimepiride) which, likeglibenclamide, are primarily eliminated by CYP2C9.

Co-administration of multiple daily doses of 5 mg linagliptin with multiple doses of 0.25 mg digoxinhad no effect on the pharmacokinetics of digoxin in healthy subjects. Therefore, linagliptin is not aninhibitor of P-glycoprotein-mediated transport in vivo.

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-state pharmacokinetics ofsimvastatin, a sensitive CYP3A4 substrate, in healthy subjects. Following administration of asupratherapeutic dose of 10 mg linagliptin concomitantly with 40 mg of simvastatin daily for 6 days,the plasma AUC of simvastatin was increased by 34%, and the plasma Cmax by 10%.

Co-administration with 5 mg linagliptin did not alter the steady-state pharmacokinetics oflevonorgestrel or ethinylestradiol.

Combination requiring precautions for use

Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsichyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoringperformed, especially at the beginning of treatment with such medicinal products. If necessary, thedose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the othermedicinal product and on its discontinuation.

Some medicinal products can adversely affect renal function which may increase the risk of lacticacidosis, e.g. NSAIDs, including selective cyclo-oxygenase (COX) II inhibitors, ACE inhibitors,angiotensin II receptor antagonists and diuretics, especially loop diuretics. When starting or using suchproducts in combination with metformin, close monitoring of renal function is necessary.

Organic cation transporters (OCT)

Metformin is a substrate of both transporters OCT1 and OCT2. Co-administration of metformin with

* Inhibitors of OCT1 (such as verapamil) may reduce efficacy of metformin.

* Inducers of OCT1 (such as rifampicin) may increase gastrointestinal absorption and efficacy ofmetformin.

* Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib,isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase inmetformin plasma concentration.

* Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renalelimination of metformin.

Caution is therefore advised, especially in patients with renal impairment, when these drugs arecoadministered with metformin, as metformin plasma concentration may increase. If needed, doseadjustment of metformin may be considered as OCT inhibitors/inducers may alter the efficacy ofmetformin.

Alcohol

Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases offasting, malnutrition or hepatic impairment.

Iodinated contrast agents

Jentadueto must be discontinued prior to or at the time of the imaging procedure and not restarted untilat least 48 hours after, provided that renal function has been re-evaluated and found to be stable, seesections 4.2 and 4.4.

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).

A limited amount of data suggests that the use of metformin in pregnant women is not associated withan increased risk of congenital malformations. Animal studies with metformin do not indicate harmfuleffects with respect to reproductive toxicity (see section 5.3).

Non-clinical reproduction studies did not indicate an additive teratogenic effect attributed to the co-administration of linagliptin and metformin.

Jentadueto should not be used during pregnancy. If the patient plans to become pregnant, or ifpregnancy occurs, treatment with Jentadueto should be discontinued and switched to insulin treatmentas soon as possible in order to lower the risk of foetal malformations associated with abnormal bloodglucose levels.

Studies in animals have shown excretion of both metformin and linagliptin into milk in lactating rats.

Metformin is excreted in human milk in small amounts. It is not known whether linagliptin is excretedinto human milk. A decision must be made whether to discontinue breast-feeding or todiscontinue/abstain from Jentadueto therapy taking into account the benefit of breast-feeding for thechild and the benefit of therapy for the woman.

The effect of Jentadueto on human fertility has not been studied. No adverse effects of linagliptin onfertility were observed in male or female rats (see section 5.3).

Jentadueto has no or negligible influence on the ability to drive and use machines. However, patientsshould be alerted to the risk of hypoglycaemia when Jentadueto is used in combination with other anti-diabetic medicinal products known to cause hypoglycaemia (e.g. sulphonylureas).

The safety of linagliptin 2.5 mg twice daily (or its bioequivalent of 5 mg once daily) in combinationwith metformin has been evaluated in over 6 800 patients with type 2 diabetes mellitus. In placebo-controlled studies, more than 1 800 patients were treated with the therapeutic dose of either 2.5 mglinagliptin twice daily (or its bioequivalent of 5 mg linagliptin once daily) in combination withmetformin for ≥ 12/24 weeks.

In the pooled analysis of the seven placebo-controlled trials, the overall incidence of adverse events inpatients treated with placebo and metformin was comparable to that seen with linagliptin 2.5 mg andmetformin (54.3 and 49.0%). Discontinuation of therapy due to adverse events was comparable inpatients who received placebo and metformin to patients treated with linagliptin and metformin (3.8%and 2.9%).

The most frequently reported adverse reaction for linagliptin plus metformin was diarrhoea (1.6%)with a comparable rate on metformin plus placebo (2.4%).

Hypoglycaemia may occur when Jentadueto is administered together with sulphonylurea (≥ 1 case per10 patients).

Adverse reactions reported in all clinical trials with the linagliptin+metformin combination or the useof the monocomponents (linagliptin or metformin) in clinical trials or from post-marketing experienceare shown below according to system organ class. Adverse reactions previously reported with one ofthe individual active substances may be potential adverse reactions with Jentadueto, even if notobserved in clinical trials with this medicinal product.

The adverse reactions are listed by system organ class and absolute frequency. Frequencies are definedas 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), or very rare (< 1/10 000) and not known (cannot be estimated from theavailable data).

Table 2: Adverse reactions reported in patients who received linagliptin+metformin alone (asmono-components or in combination) or as add-on to other anti-diabetic therapies inclinical trial and from post-marketing experience

System organ class Frequency of adverse reaction

Adverse reaction

Nasopharyngitis uncommon

Hypersensitivity uncommon(e.g. bronchial hyperreactivity)

Hypoglycaemia 1 very common

Lactic acidosis § very rare

Vitamin B12 decrease/deficiency §, † common

Taste disturbance § common

Cough uncommon

Decreased appetite uncommon

Diarrhoea common

System organ class Frequency of adverse reaction

Adverse reaction

Nasopharyngitis uncommon

Nausea common

Pancreatitis rare #

Vomiting uncommon

Constipation 2 uncommon

Abdominal pain § very common

Liver function disorders 2 uncommon

Hepatitis § very rare

Angioedema rare

Urticaria rare

Erythema§ very rare

Rash uncommon

Pruritus uncommon

Bullous pemphigoid rare #

Amylase increased uncommon

Lipase increased* common

* Based on lipase elevations > 3 × ULN observed in clinical trials# Based on Linagliptin cardiovascular and renal safety study (CARMELINA), see also below§ Identified adverse reactions of metformin monotherapy. Refer to Summary of Product Characteristics formetformin for additional information† See section 4.41 Adverse reaction observed in combination of Jentadueto with sulphonylurea2 Adverse reaction observed in combination of Jentadueto with insulin

In one study linagliptin was given as add-on to metformin plus sulphonylurea. When linagliptin andmetformin were administered in combination with a sulphonylurea, hypoglycaemia was the mostfrequently reported adverse event (linagliptin plus metformin plus sulphonylurea 23.9% and 16.0% inplacebo plus metformin plus sulphonylurea).

When linagliptin and metformin were administered in combination with insulin, hypoglycaemia wasthe most frequently reported adverse event, but occurred at comparable rate when placebo andmetformin were combined with insulin (linagliptin plus metformin plus insulin 29.5% and 30.9% inthe placebo plus metformin plus insulin group) with a low rate of severe (requiring assistance)episodes (1.5% and 0.9%).

Other adverse reactions

Gastrointestinal disorders such as, nausea, vomiting, diarrhoea and decreased appetite and abdominalpain occur most frequently during initiation of therapy with Jentadueto or metformin hydrochlorideand resolve spontaneously in most cases. For prevention, it is recommended that Jentadueto be takenduring or after meals. A slow increase in dose of metformin hydrochloride may also improvegastrointestinal tolerability.

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.

Linagliptin

During controlled clinical trials in healthy subjects, single doses of up to 600 mg linagliptin(equivalent to 120 times the recommended dose) were not associated with a dose dependent increasein adverse events. There is no experience with doses above 600 mg in humans.

Hypoglycaemia has not been seen with metformin hydrochloride doses of up to 85 g, although lacticacidosis has occurred in such circumstances. High overdose of metformin hydrochloride orconcomitant risks may lead to lactic acidosis. Lactic acidosis is a medical emergency and must betreated in hospital. The most effective method to remove lactate and metformin hydrochloride ishaemodialysis.

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, combinations of oral blood glucose loweringdrugs, ATC code: A10BD11

Jentadueto combines two antihyperglycaemic medicinal products with complementary mechanisms ofaction to improve glycaemic control in patients with type 2 diabetes: linagliptin, a dipeptidylpeptidase 4 (DPP-4) inhibitor, and metformin hydrochloride, a member of the biguanide class.

Linagliptin

Linagliptin is an inhibitor of the enzyme DPP-4 (Dipeptidyl peptidase 4) an enzyme which is involvedin the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by the enzyme DPP-4.

Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretinsare secreted at a low basal level throughout the day and levels rise immediately after meal intake.

GLP-1 and GIP increase insulin biosynthesis and secretion from pancreatic beta cells in the presenceof normal and elevated blood glucose levels. Furthermore GLP-1 also reduces glucagon secretion frompancreatic alpha cells, resulting in a reduction in hepatic glucose output. Linagliptin binds veryeffectively to DPP-4 in a reversible manner and thus leads to a sustained increase and a prolongationof active incretin levels. Linagliptin glucose-dependently increases insulin secretion and lowersglucagon secretion thus resulting in an overall improvement in the glucose homeostasis. Linagliptinbinds selectively to DPP-4 and exhibits a > 10 000 fold selectivity versus DPP-8 or DPP-9 activityin vitro.

Metformin hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal andpostprandial plasma glucose. It does not stimulate insulin secretion and therefore does not producehypoglycaemia.

Metformin hydrochloride may act via 3 mechanisms:

(1) reduction of hepatic glucose production by inhibiting gluconeogenesis and glycogenolysis,(2) in muscle, by increasing insulin sensitivity, improving peripheral glucose uptake and utilisation,(3) and delay of intestinal glucose absorption.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin hydrochloride increases the transport capacity of all types of membrane glucosetransporters (GLUTs) known to date.

In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effectson lipid metabolism. This has been shown at therapeutic doses in controlled, medium-term or long-term clinical studies: metformin hydrochloride reduces total cholesterol, LDL cholesterol andtriglyceride levels.

Linagliptin as add-on to metformin therapy

The efficacy and safety of linagliptin in combination with metformin in patients with insufficientglycaemic control on metformin monotherapy was evaluated in a double-blind placebo-controlledstudy of 24 weeks duration. Linagliptin added to metformin 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) by -21.1 mg/dl and 2-hour post-prandial glucose (PPG) by -67.1 mg/dl compared to placebo, as well as a greater portion of patientsachieving a target HbA1c of < 7.0% (28.3% on linagliptin versus 11.4% on placebo). The observedincidence of hypoglycaemia in patients treated with linagliptin was similar to placebo. Body weightdid not differ significantly between the groups.

In a 24-week placebo-controlled factorial study of initial therapy, linagliptin 2.5 mg twice daily incombination with metformin (500 mg or 1 000 mg twice daily) provided significant improvements inglycaemic parameters compared with either monotherapy as summarised in Table 3 (mean baseline

HbA1c 8.65%).

Table 3: Glycaemic parameters at final visit (24-week study) for linagliptin and metformin, aloneand in combination in patients with type 2 diabetes mellitus inadequately controlled ondiet and exercise

Placebo Linagliptin Metformin Linagliptin Metformin Linagliptin5 mg Once HCl 2.5 mg HCl 2.5 mg

Daily1 500 mg Twice 1 000 mg Twice

Twice Daily1 + Twice Daily1 +

Daily Metformin Daily Metformin

HCl HCl500 mg 1 000 mg

Twice Twice

Daily Daily

HbA1c (%)

Number of patients n = 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 frombaseline (adjusted 0.1 -0.5 -0.6 -1.2 -1.1 -1.6mean)

Difference from -- -0.6 -0.8 -1.3 -1.2 -1.7placebo (adjusted (-0.9, -0.3) (-1.0, -0.5) (-1.6, -1.1) (-1.5, -0.9) (-2.0, -1.4)mean) (95% CI)

Patients (n, %)achieving HbA1c 7 (10.8) 14 (10.4) 27 (19.1) 42 (30.7) 43 (31.2) 76 (54.3)< 7%

Patients (%)receiving rescue 29.2 11.1 13.5 7.3 8.0 4.3treatment

FPG (mg/dL)

Number of patients n = 61 n = 134 n = 136 n = 135 n = 132 n = 136

Baseline (mean) 203 195 191 199 191 196

Change frombaseline (adjusted 10 -9 -16 -33 -32 -49mean)

Difference from -- -19 -26 -43 -42 -60placebo (adjusted (-31, -6) (-38, -14) (-56, -31) (-55, -30) (-72, -47)mean) (95% CI)1 Total daily dose of linagliptin is equal to 5 mg

Mean reductions from baseline in HbA1c were generally greater for patients with higher baseline

HbA1c values. Effects on plasma lipids were generally neutral. The decrease in body weight with thecombination of linagliptin and metformin was similar to that observed for metformin alone or placebo;there was no change in weight from baseline for patients on linagliptin alone. The incidence ofhypoglycaemia was similar across treatment groups (placebo 1.4%, linagliptin 5 mg 0%, metformin2.1%, and linagliptin 2.5 mg plus metformin twice daily 1.4%).

The efficacy and safety of linagliptin 2.5 mg twice daily versus 5 mg once daily in combination withmetformin in patients with insufficient glycaemic control on metformin monotherapy was evaluated ina double-blind placebo-controlled study of 12 weeks duration. Linagliptin 5 mg once daily and 2.5 mgtwice daily provided comparable (CI: -0.07; 0.19) significant HbA1c reductions of -0.80% (frombaseline 7.98%), and -0.74% (from baseline 7.96%) compared to placebo. The observed incidence ofhypoglycaemia in patients treated with linagliptin was similar to placebo. Body weight did not differsignificantly between the groups.

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 achieving a target HbA1c of < 7.0% (31.2% on linagliptin versus 9.2% onplacebo), and also for fasting plasma glucose (FPG) with -12.7 mg/dl reduction compared to placebo.

Body weight did not differ significantly between the groups.

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 in combination with metformin and insulin

A 24-week placebo-controlled study was conducted to evaluate the efficacy and safety of linagliptin(5 mg once daily) added to insulin with or without metformin. 83% of patients were taking metforminin combination with insulin in this trial. Linagliptin in combination with metformin plus insulinprovided significant improvements in HbA1c in this subgroup with -0.68% (CI: -0.78; -0,57) adjustedmean change from baseline (mean baseline HbA1c 8.28%) compared to placebo in combination withmetformin plus insulin. There was no meaningful change from baseline in body weight in eithergroup.

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 versus +1.29 kg).

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 anti-diabetic therapy were kept stable during thefirst 12 weeks, after which adjustments were permitted. Linagliptin provided significant improvementsin 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 toplacebo. Body weight did not differ significantly between the groups.

In a pooled analysis of elderly (age ≥ 70 years) patients with type 2 diabetes (n = 183) who weretaking both metformin and basal insulin as background therapy, linagliptin in combination withmetformin plus insulin provided significant improvements in HbA1c parameters with -0.81%(CI: -1.01; -0.61) adjusted mean change from baseline (mean baseline HbA1c 8.13%) compared toplacebo in combination with metformin plus insulin.

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 standard of care, did not increase therisk of 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 tostandard of care without linagliptin in patients with type 2 diabetes (table 4).

Table 4: 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 per1 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,composite 1.17)**(Cardiovasculardeath, non-fatal MI,non-fatal stroke)

Secondary renal 327 (9.4) 48.9 306 (8.8) 46.6 1.04 (0.89,composite (renal 1.22)death, ESRD, 40%sustained decreasein eGFR)

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,heart failure 1.08)

* 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 included2 089 (35%) patients with cardiovascular disease and 1 130 (19%) patients with renal impairment withan eGFR < 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, when added to standard of care, did not increasethe risk of major adverse cardiovascular events (table 5) as compared to glimepiride. Results wereconsistent for patients treated with or without metformin.

Table 5: 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,composite 1.14)**(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 prospective randomised (UKPDS) study has established the long-term benefit of intensive bloodglucose control in type 2 diabetes. Analysis of the results for overweight patients treated withmetformin after failure of diet alone showed:

* a significant reduction of the absolute risk of any diabetes-related complication in the metformingroup (29.8 events/1 000 patient-years) versus diet alone (43.3 events/1 000 patient-years),p = 0.0023, and versus the combined sulphonylurea and insulin monotherapy groups(40.1 events/1 000 patient-years), p = 0.0034,

* a significant reduction of the absolute risk of any diabetes-related mortality: metformin7.5 events/1 000 patient-years, diet alone 12.7 events/1 000 patient-years, p = 0.017,

* a significant reduction of the absolute risk of overall mortality: metformin13.5 events/1 000 patient-years versus diet alone 20.6 events/1 000 patient-years, (p = 0.011),and versus the combined sulphonylurea and insulin monotherapy groups18.9 events/1 000 patient-years (p = 0.021),

* a significant reduction in the absolute risk of myocardial infarction: metformin11 events/1 000 patient-years, diet alone 18 events/1 000 patient-years, (p = 0.01).

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. 91% ofpatients in the study were on background therapy with metformin as adjunct to diet and exercise.

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).

Bioequivalence studies in healthy subjects demonstrated that the Jentadueto (linagliptin/metforminhydrochloride) combination tablets are bioequivalent to co-administration of linagliptin and metforminhydrochloride as individual tablets.

Administration of Jentadueto 2.5/1 000 mg with food resulted in no change in overall exposure oflinagliptin. With metformin there was no change in AUC, however mean peak serum concentration ofmetformin was decreased by 18% when administered with food. A delayed time to peak serumconcentrations by 2 hours was observed for metformin under fed conditions. These changes are notlikely to be clinically meaningful.

The following statements reflect the pharmacokinetic properties of the individual active substances of

Jentadueto.

Linagliptin

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 active substance.

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-IV, the pharmacokinetics of linagliptin based on total exposure is not linear; indeed total plasma

AUC of linagliptin increased in a less than dose-proportional manner, while unbound AUC increasesin a roughly 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 noinfluence on AUC0-72h was observed. No clinically relevant effect of Cmax and Tmax changes isexpected; 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 20-30% 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.

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. No doseadjustment of linagliptin is recommended in patients with renal impairment; therefore, linagliptin maybe continued as a single entity tablet at the same total daily dose of 5 mg if Jentadueto is discontinueddue to evidence of renal impairment.

In patients with mild moderate and severe hepatic impairment (according to the Child-Pughclassification), mean AUC and Cmax of linagliptin were similar to healthy matched controls followingadministration of multiple 5 mg doses of linagliptin.

Body Mass Index (BMI)

Body mass index had no clinically relevant effect on the pharmacokinetics of linagliptin based on apopulation pharmacokinetic analysis of Phase I and Phase II data. The clinical trials before marketingauthorization have been performed up to a BMI equal to 40 kg/m2.

Gender had no clinically relevant effect on the pharmacokinetics of linagliptin based on a populationpharmacokinetic analysis of Phase I and Phase II data.

Age did not have a clinically relevant impact on the pharmacokinetics of linagliptin based on apopulation pharmacokinetic analysis of Phase I and Phase II data. Older subjects (65 to 80 years,oldest patient was 78 years) had comparable plasma concentrations of linagliptin compared to youngersubjects. Linagliptin trough concentrations were also measured in elderly (age ≥ 70 years) with type 2diabetes in a phase III study of 24 weeks duration. Linagliptin concentrations in this study were withinthe range of values previously observed in younger type 2 diabetes patients.

A paediatric Phase 2 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 3 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.

Race had no obvious effect on the plasma concentrations of linagliptin based on a composite analysisof available pharmacokinetic data, including patients of Caucasian, Hispanic, African, and Asianorigin. In addition the pharmacokinetic characteristics of linagliptin were found to be similar indedicated phase I studies in Japanese, Chinese and Caucasian healthy subjects and African Americantype 2 diabetes patients.

After an oral dose of metformin, Tmax is reached in 2.5 hours. Absolute bioavailability of a 500 mg or850 mg metformin hydrochloride tablet is approximately 50-60% in healthy subjects. After an oraldose, the non-absorbed fraction recovered in faeces was 20-30%.

After oral administration, metformin hydrochloride absorption is saturable and incomplete. It isassumed that the pharmacokinetics of metformin hydrochloride absorption are non-linear.

At the recommended metformin hydrochloride doses and dosing schedules, steady-state plasmaconcentrations are reached within 24 to 48 hours and are generally less than 1 microgram/mL. Incontrolled clinical trials, maximum metformin hydrochloride plasma levels (Cmax) did not exceed5 microgram/mL, even at maximum doses.

Food decreases the extent and slightly delays the absorption of metformin hydrochloride. Followingadministration of a dose of 850 mg, a 40% lower plasma peak concentration, a 25% decrease in AUC(area under the curve) and a 35 minute prolongation of the time to peak plasma concentration wereobserved. The clinical relevance of these decreases is unknown.

Plasma protein binding is negligible. Metformin hydrochloride partitions into erythrocytes. The bloodpeak is lower than the plasma peak and appears at approximately the same time. The red blood cellsmost likely represent a secondary compartment of distribution. The mean volume of distribution (Vd)ranged between 63-276 L.

Metformin hydrochloride is excreted unchanged in the urine. No metabolites have been identified inhumans.

Renal clearance of metformin hydrochloride is > 400 mL/min, indicating that metforminhydrochloride is eliminated by glomerular filtration and tubular secretion. Following an oral dose, theapparent terminal elimination half-life is approximately 6.5 hours.

When renal function is impaired, renal clearance is decreased in proportion to that of creatinine andthus the elimination half-life is prolonged, leading to increased levels of metformin hydrochloride inplasma.

Single dose study: after single doses of metformin hydrochloride 500 mg, paediatric patients haveshown a similar pharmacokinetic profile to that observed in healthy adults.

Multiple-dose study: data are restricted to one study. After repeated doses of 500 mg twice daily for7 days in paediatric patients the peak plasma concentration (Cmax) and systemic exposure (AUC0-t)were reduced by approximately 33% and 40%, respectively compared to diabetic adults who receivedrepeated doses of 500 mg twice daily for 14 days. As the dose is individually titrated based onglycaemic control, this is of limited clinical relevance.

Linagliptin plus metformin

General toxicity studies in rats for up to 13 weeks were performed with the co-administration oflinagliptin and metformin. The only observed interaction between linagliptin and metformin was areduction of body weight gain. No other additive toxicity caused by the combination of linagliptin andmetformin was observed at AUC exposure levels up to 2 and 23 times human exposure, respectively.

An embryofetal development study in pregnant rats did not indicate a teratogenic effect attributed tothe co-administration of linagliptin and metformin at AUC exposure levels up to 4 and 30 timeshuman exposure, respectively.

Linagliptin

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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

Arginine

Copovidone

Magnesium stearate

Maize starch

Silica, colloidal anhydrous

Jentadueto 2.5 mg/850 mg film-coated tablets

Hypromellose

Titanium dioxide (E171)

Talc

Yellow iron oxide (E172)

Red iron oxide (E172)

Jentadueto 2.5 mg/1 000 mg film-coated tablets

Hypromellose

Titanium dioxide (E171)

Talc

Red iron oxide (E172)

Not applicable.

3 years.

This medicinal product does not require any special temperature storage conditions.

Store in the original package in order to protect from moisture.

Keep the bottle tightly closed in order to protect from moisture.

- Pack sizes of 10 × 1, 14 × 1, 28 × 1, 30 × 1, 56 × 1, 60 × 1, 84 × 1, 90 × 1, 98 × 1, 100 × 1 and120 × 1 film-coated tablets and multipacks containing 120 (2 packs of 60 × 1), 180 (2 packs of90 × 1), 180 (3 packs of 60 × 1) and 200 (2 packs of 100 × 1) film-coated tablets in aluminiumlidding foil and PVC/polychlorotrifluoro ethylene/PVC based forming foil perforated unit doseblisters.

- High-Density PolyEthylene (HDPE) bottle with plastic screw cap and a seal liner (aluminium-polyester foil laminate) and a silica gel desiccant. Pack sizes of 14, 60 and 180 film-coatedtablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Boehringer Ingelheim International GmbH,

Binger Str. 173,55216 Ingelheim am Rhein,

Germany.

Jentadueto 2.5 mg/850 mg film-coated tablets

EU/1/12/780/001 (10 × 1 film-coated tablets)

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Jentadueto 2.5 mg/1 000 mg film-coated tablets

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EU/1/12/780/026 (14 film-coated tablets, bottle)

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EU/1/12/780/033 (180 (2 × 90 × 1) film-coated tablets)

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Date of first authorisation: 20 July 2012

Date of latest renewal: 22 March 2017

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

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