linagliptin/metformin hydrochloride: prescribing information – dosing, contraindications, interactions, side effects

Jentadueto is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve 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, in patients inadequately controlled with metformin and these medicinal products
- in patients already being treated with the combination of linagliptin and metformin as separate tablets.
(see sections 4.4, 4.5 and 5.1 for available data on different combinations).

Posology
Adults with normal renal function (GFR ≥ 90 mL/min)
The dose of antihyperglycaemic therapy with Jentadueto should be individualised on the basis of the patient’s current regimen, effectiveness, and tolerability, while not exceeding the maximum recommended 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 Jentadueto should provide linagliptin dosed as 2.5 mg twice daily (5 mg total daily dose) plus the dose of metformin already being taken.

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

Patients inadequately controlled on dual combination therapy with the maximal tolerated dose of metformin 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 metformin hydrochloride is used in combination with a sulphonylurea, a lower dose of the sulphonylurea may be required to reduce the risk of hypoglycaemia (see section 4.4).

Patients inadequately controlled on dual combination therapy with insulin and the maximal tolerated dose 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 metformin hydrochloride is used in combination with insulin, a lower dose of insulin may be required to reduce the risk of hypoglycaemia (see section 4.4).

For the different doses of metformin, Jentadueto is available in strengths of 2.5 mg linagliptin plus 850 mg metformin hydrochloride and 2.5 mg linagliptin plus 1 000 mg metformin hydrochloride.

Special populations
Elderly
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).

Renal impairment
A GFR should be assessed before initiation of treatment with metformin containing products and at least annually thereafter. In patients at an increased risk of further progression of renal impairment and in 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 considering initiation of metformin in patients with GFR< 60 mL/min.
If no adequate strength of Jentadueto is available, individual monocomponents should be used instead of the fixed dose combination.

Table 1:
Posology for renally impaired patients

GFR mL/min
Metformin
Linagliptin
60-89
Maximum daily dose is 3 000 mg.
Dose reduction may be considered in relation to declining renal function.
No dose adjustment
45-59
Maximum daily dose is 2 000 mg
The starting dose is at most half of the maximum dose.
No dose adjustment
30-44
Maximum daily dose is 1 000 mg.
The starting dose is at most half of the maximum dose.
No dose adjustment
< 30
Metformin is contraindicated
No dose adjustment

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

Paediatric population
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.

Method of administration
Jentadueto should be taken twice daily with meals to reduce the gastrointestinal adverse reactions associated with metformin.
All patients should continue their diet with an adequate distribution of carbohydrate intake during the day. 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 dose should not be taken at the same time. In that case, the missed dose should be skipped.

Number of patients n = 61 n = 134 n = 136 n = 135 n = 132 n = 136
Baseline (mean)
Change from baseline (adjusted mean)
-9
-16
-33
-32
-49
Difference from placebo (adjusted mean) (95% CI)
--
-19
(-31, -6)
-26
(-38, -14)
-43
(-56, -31)
-42
(-55, -30)
-60
(-72, -47)
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 the combination 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 of hypoglycaemia was similar across treatment groups (placebo 1.4%, linagliptin 5 mg 0%, metformin 2.1%, 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 with metformin in patients with insufficient glycaemic control on metformin monotherapy was evaluated in a double-blind placebo-controlled study of 12 weeks duration. Linagliptin 5 mg once daily and 2.5 mg twice daily provided comparable (CI: -0.07; 0.19) significant HbA1c reductions of -0.80% (from baseline 7.98%), and -0.74% (from baseline 7.96%) compared to placebo. The observed incidence of hypoglycaemia in patients treated with linagliptin was similar to placebo. Body weight did not differ significantly 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 safety of linagliptin 5 mg to placebo, in patients not sufficiently treated with a combination with metformin

and a sulphonylurea. Linagliptin provided significant improvements in HbA1c (-0.62% change compared to placebo), from a mean baseline HbA1c of 8.14%. Linagliptin also showed significant improvements in patients achieving a target HbA1c of < 7.0% (31.2% on linagliptin versus 9.2% on placebo), 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 HbA1c reductions 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% and treated 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 metformin in combination with insulin in this trial. Linagliptin in combination with metformin plus insulin provided significant improvements in HbA1c in this subgroup with -0.68% (CI: -0.78; -0,57) adjusted mean change from baseline (mean baseline HbA1c 8.28%) compared to placebo in combination with metformin plus insulin. There was no meaningful change from baseline in body weight in either group.

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 (mean dose 3 mg) in patients with inadequate glycaemic control on metformin monotherapy, mean reductions in 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 in the glimepiride group (36.1%). Patients treated with linagliptin exhibited a significant mean decrease from baseline in body weight compared to a significant weight gain in patients administered glimepiride (-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 in a double-blind study of 24 weeks duration. Patients received metformin and/or sulphonylurea and/or insulin as background therapy. Doses of background anti-diabetic therapy were kept stable during the first 12 weeks, after which adjustments were permitted. Linagliptin provided significant improvements 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.

In a pooled analysis of elderly (age ≥ 70 years) patients with type 2 diabetes (n = 183) who were taking both metformin and basal insulin as background therapy, linagliptin in combination with metformin 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 to placebo 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 risk evidenced by a history of established macrovascular or renal disease who were treated with linagliptin 5 mg (3 494) or placebo (3 485) added to standard of care targeting regional standards for HbA1c, CV risk factors and renal disease. The study population included 1 211 (17.4%) patients ≥ 75 years of age and 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) and 15% 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 which was 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 or sustained 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 the risk of major adverse cardiovascular events or renal outcome events. There was no increased risk in hospitalization for heart failure which was an additional adjudicated endpoint observed compared to standard 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
Subjects (%)
Incidence
Rate per

Summary of the safety profile
The safety of linagliptin 2.5 mg twice daily (or its bioequivalent of 5 mg once daily) in combination with 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 mg linagliptin twice daily (or its bioequivalent of 5 mg linagliptin once daily) in combination with metformin for ≥ 12/24 weeks.

In the pooled analysis of the seven placebo-controlled trials, the overall incidence of adverse events in patients treated with placebo and metformin was comparable to that seen with linagliptin 2.5 mg and metformin (54.3 and 49.0%). Discontinuation of therapy due to adverse events was comparable in patients 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 per 10 patients).

Tabulated list of adverse reactions
Adverse reactions reported in all clinical trials with the linagliptin+metformin combination or the use of the monocomponents (linagliptin or metformin) in clinical trials or from post-marketing experience are shown below according to system organ class. Adverse reactions previously reported with one of the individual active substances may be potential adverse reactions with Jentadueto, even if not observed in clinical trials with this medicinal product.

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

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

System organ class
Adverse reaction
Frequency of adverse reaction
Infections and infestations

Nasopharyngitis uncommon
Immune system disorders

Hypersensitivity
(e.g. bronchial hyperreactivity) uncommon
Metabolism and nutrition disorders

Hypoglycaemia 1 very common
Lactic acidosis § very rare
Vitamin B12 decrease/deficiency §, † common
Nervous system disorders

Taste disturbance § common
Respiratory, thoracic and mediastinal disorders

Cough uncommon
Gastrointestinal disorders

Decreased appetite uncommon
Diarrhoea common

System organ class
Adverse reaction
Frequency of adverse reaction
Infections and infestations

Nasopharyngitis uncommon
Nausea common
Pancreatitis rare #
Vomiting uncommon
Constipation 2 uncommon
Abdominal pain § very common
Hepatobiliary disorders

Liver function disorders 2 uncommon
Hepatitis § very rare
Skin and subcutaneous tissue disorders

Angioedema rare
Urticaria rare
Erythema§ very rare
Rash uncommon
Pruritus uncommon
Bullous pemphigoid rare #
Investigations

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 for metformin for additional information † See section 4.4 Adverse reaction observed in combination of Jentadueto with sulphonylurea Adverse reaction observed in combination of Jentadueto with insulin

Description of selected adverse reactions
Hypoglycaemia
In one study linagliptin was given as add-on to metformin plus sulphonylurea. When linagliptin and metformin were administered in combination with a sulphonylurea, hypoglycaemia was the most frequently reported adverse event (linagliptin plus metformin plus sulphonylurea 23.9% and 16.0% in placebo plus metformin plus sulphonylurea).

When linagliptin and metformin were administered in combination with insulin, hypoglycaemia was the most frequently reported adverse event, but occurred at comparable rate when placebo and metformin were combined with insulin (linagliptin plus metformin plus insulin 29.5% and 30.9% in the 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 abdominal pain occur most frequently during initiation of therapy with Jentadueto or metformin hydrochloride and resolve spontaneously in most cases. For prevention, it is recommended that Jentadueto be taken during or after meals. A slow increase in dose of metformin hydrochloride may also improve gastrointestinal tolerability.

Linagliptin cardiovascular and renal safety study (CARMELINA)
The CARMELINA study evaluated the cardiovascular and renal safety of linagliptin versus placebo in patients with type 2 diabetes and with increased CV risk evidenced by a history of established macrovascular or renal disease (see section 5.1). The study included 3 494 patients treated with linagliptin (5 mg) and 3 485 patients treated with placebo. Both treatments were added to standard of care targeting regional standards for HbA1c and CV risk factors. The overall incidence of adverse events and serious adverse events in patients receiving linagliptin was similar to that in patients

receiving placebo. Safety data from this study was in line with previous known safety profile of linagliptin.

In the treated population, severe hypoglycaemic events (requiring assistance) were reported in 3.0% of patients on linagliptin and in 3.1% on placebo. Among patients who were using sulfonylurea at baseline, the incidence of severe hypoglycaemia was 2.0% in linagliptin-treated patients and 1.7% in placebo treated patients. Among patients who were using insulin at baseline, the incidence of severe hypoglycaemia 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 patients treated 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 with linagliptin and in no patient treated with placebo.

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

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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

Hypoglycaemia
When linagliptin was added to a sulphonylurea on a background of metformin, the incidence of hypoglycaemia 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 the sulphonylurea or insulin may be considered (see section 4.2).

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

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

In case of dehydration (severe diarrhoea or vomiting, fever or reduced fluid intake), metformin should be 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 lactic acidosis are excessive alcohol intake, hepatic impairment, inadequately controlled diabetes, ketosis, prolonged fasting and any conditions associated with hypoxia, as well as concomitant use of medicinal products 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 is

characterised by acidotic dyspnea, abdominal pain, muscle cramps, asthenia and hypothermia followed by coma. In case of suspected symptoms, the patient should stop taking metformin and seek immediate 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 neurologic complications which may lead to worsening of the disease.

In case of signs and symptoms suggestive of MELAS syndrome or MIDD after the intake of metformin, treatment with metformin should be withdrawn immediately and prompt diagnostic evaluation 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 be discontinued prior to or at the time of the imaging procedure and not restarted until at least 48 hours after, provided that renal function has been re-evaluated and found to be stable, see sections 4.2 and

No interaction studies have been performed. However, such studies have been conducted with the individual active substances, i.e. linagliptin and metformin. Co-administration of multiple doses of linagliptin and metformin did not meaningfully alter the pharmacokinetics of either linagliptin or metformin 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 digoxin with low potency. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely 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 by coadministered medicinal products is low.

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

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

Ritonavir:
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 linagliptin approximately twofold and threefold, respectively. The unbound concentrations, which are usually 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 and without ritonavir indicated that the increase in exposure will not be associated with an increased accumulation. These changes in linagliptin pharmacokinetics were not considered to be clinically relevant. Therefore, clinically relevant interactions would not be expected with other P-glycoprotein/CYP3A4 inhibitors.

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 AUC and Cmax

respectively, and about 30% decreased DPP-4 inhibition at trough. Thus full efficacy of linagliptin in combination with strong P-gp inducers might not be achieved, particularly if these are administered long-term. Co-administration with other potent inducers of P-glycoprotein and CYP3A4, such as carbamazepine, 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 the pharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin or oral contraceptives providing in vivo evidence of a low propensity for causing interactions with substrates 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 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 mg glibenclamide (glyburide) resulted in clinically not relevant reduction of 14% of both AUC and Cmax of glibenclamide. Because glibenclamide is primarily metabolised by CYP2C9, these data also support the conclusion that linagliptin is not a CYP2C9 inhibitor. Clinically meaningful interactions would not be expected with other sulphonylureas (e.g., glipizide, tolbutamide, and glimepiride) 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 mg digoxin had no effect on the pharmacokinetics of digoxin in healthy subjects. Therefore, linagliptin is 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-state pharmacokinetics of simvastatin, a sensitive CYP3A4 substrate, in healthy subjects. Following administration of a supratherapeutic 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%.

Oral contraceptives:
Co-administration with 5 mg linagliptin did not alter the steady-state pharmacokinetics of levonorgestrel or ethinylestradiol.

Metformin
Combination requiring precautions for use
Glucocorticoids (given by systemic and local routes), beta-2-agonists, and diuretics have intrinsic hyperglycaemic activity. The patient should be informed and more frequent blood glucose monitoring performed, especially at the beginning of treatment with such medicinal products. If necessary, the dose of the anti-hyperglycaemic medicinal product should be adjusted during therapy with the other medicinal product and on its discontinuation.

Some medicinal products can adversely affect renal function which may increase the risk of lactic acidosis, 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 such products 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 of metformin.
- Inhibitors of OCT2 (such as cimetidine, dolutegravir, ranolazine, trimethoprime, vandetanib, isavuconazole) may decrease the renal elimination of metformin and thus lead to an increase in metformin plasma concentration.
- Inhibitors of both OCT1 and OCT2 (such as crizotinib, olaparib) may alter efficacy and renal elimination of metformin.

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

Concomitant use not recommended
Alcohol
Alcohol intoxication is associated with an increased risk of lactic acidosis, particularly in cases of fasting, malnutrition or hepatic impairment.

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

Pregnancy
The use of linagliptin has not been studied in pregnant women. Animal studies do not indicate direct or 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 with an increased risk of congenital malformations. Animal studies with metformin do not indicate harmful effects 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 if pregnancy occurs, treatment with Jentadueto should be discontinued and switched to insulin treatment as soon as possible in order to lower the risk of foetal malformations associated with abnormal blood glucose levels.

Breast-feeding
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 excreted into human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Jentadueto therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility
The effect of Jentadueto on human fertility has not been studied. No adverse effects of linagliptin on fertility 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, patients should 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).

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 increase in adverse events. There is no experience with doses above 600 mg in humans.

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

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

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Drugs used in diabetes, combinations of oral blood glucose lowering drugs, ATC code: A10BD11

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

Linagliptin
Mechanism of action
Linagliptin is an inhibitor of the enzyme DPP-4 (Dipeptidyl peptidase 4) an enzyme which is involved in 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. Incretins are 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 presence of normal and elevated blood glucose levels. Furthermore GLP-1 also reduces glucagon 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 sustained increase and a prolongation of active incretin levels. Linagliptin glucose-dependently increases insulin secretion and lowers glucagon secretion thus resulting in an overall improvement in the glucose homeostasis. Linagliptin binds selectively to DPP-4 and exhibits a > 10 000 fold selectivity versus DPP-8 or DPP-9 activity in vitro.

Metformin
Mechanism of action
Metformin hydrochloride is a biguanide with antihyperglycaemic effects, lowering both basal and postprandial plasma glucose. It does not stimulate insulin secretion and therefore does not produce hypoglycaemia.

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 glucose transporters (GLUTs) known to date.

In humans, independently of its action on glycaemia, metformin hydrochloride has favourable effects on 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 and triglyceride levels.

Clinical efficacy and safety

Linagliptin as add-on to metformin therapy

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

Administration of Jentadueto 2.5/1 000 mg with food resulted in no change in overall exposure of linagliptin. With metformin there was no change in AUC, however mean peak serum concentration of metformin was decreased by 18% when administered with food. A delayed time to peak serum concentrations by 2 hours was observed for metformin under fed conditions. These changes are not likely 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 patients with 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 hours post-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, tight binding of linagliptin to DPP-4 and does not contribute to the accumulation of the active substance.