4.1. Therapeutic indications

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).

4.2. Posology and method of administration

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.

4.3. Contraindications

• 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 chronic disease) such as: decompensated heart failure, respiratory failure, recent myocardial infarction, shock.

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

4.4. Special warnings and precautions for use

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 4.5.

Renal function

GFR should be assessed before treatment initiation and regularly thereafter, see section 4.2. Metformin is contraindicated in patients with GFR< 30 mL/min and should be temporarily discontinued in the presence 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 stable chronic 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).

Surgery

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 nutrition and provided that renal function has been re-evaluated and found to be stable.

Elderly

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 poorly defined 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 stopped immediately and other appropriate corrective measures initiated.

Acute pancreatitis

Use of DPP-4 inhibitors has been associated with a risk of developing acute pancreatitis. Acute pancreatitis 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 was reported 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 is suspected, Jentadueto should be discontinued; if acute pancreatitis is confirmed, Jentadueto should not be 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 on placebo. 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 with increasing metformin dose, treatment duration, and/or in patients with risk factors known to cause vitamin B12 deficiency. In case of suspicion of vitamin B12 deficiency (such as anaemia or neuropathy), vitamin B12 serum levels should be monitored. Periodic vitamin B12 monitoring could be necessary in patients with risk factors for vitamin B12 deficiency. Metformin therapy should be continued for as long as it is tolerated and not contra-indicated and appropriate corrective treatment for vitamin B12 deficiency provided in line with current clinical guidelines.

4.5. Interaction with other medicinal products and other forms of interaction

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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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).

4.8. Undesirable effects

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

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

1 Adverse reaction observed in combination of Jentadueto with sulphonylurea

2 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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

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.