4.1. Therapeutic indications

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

monotherapy

• when metformin is inappropriate due to intolerance, or contraindicated due to renal impairment.

combination therapy

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

4.2. Posology and method of administration

Posology

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

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

Special populations

Renal impairment

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

Hepatic impairment

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

Elderly

No dose adjustment is necessary based on age.

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

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

4.3. Contraindications

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

4.4. Special warnings and precautions for use

General

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

Hypoglycaemia

Linagliptin alone showed a comparable incidence of hypoglycaemia to placebo.

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

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

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

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, linagliptin should be discontinued; if acute pancreatitis is confirmed, linagliptin 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, linagliptin should be discontinued.

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

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 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 co‑administered medicinal products is low.

Rifampicin: multiple co-administration of 5 mg linagliptin with rifampicin, a potent inductor of P‑glycoprotein and CYP3A4, resulted in a 39.6% and 43.8% decreased linagliptin steady-state 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.

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 be not 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.

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

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

Effects of linagliptin on other medicinal products

In clinical studies, as described below, linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin or oral contraceptives providing in vivo evidence of a low propensity for causing medicinal product 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, an OCT substrate, had no relevant effect on the pharmacokinetics of metformin in healthy volunteers. Therefore, linagliptin is not an inhibitor of OCT-mediated transport.

Sulphonylureas: co-administration of multiple oral doses of 5 mg linagliptin and a single oral dose 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 volunteers. 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 volunteers. 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.

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). As a precautionary measure, it is preferable to avoid the use of linagliptin during pregnancy.

Breast-feeding

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

Fertility

No studies on the effect on human fertility have been conducted for linagliptin. Animal studies do not indicate direct or indirect harmful effects with respect to fertility (see section 5.3).

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

In the pooled analysis of the placebo-controlled trials, the overall incidence of adverse events in patients treated with placebo was similar to linagliptin 5 mg (63.4% versus 59.1%). Discontinuation of therapy due to adverse events was higher in patients who received placebo as compared to linagliptin 5 mg (4.3% versus 3.4%).

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

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

Tabulated list of adverse reactions

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

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

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

- monotherapy with ≥ 12 week duration

- add-on to metformin

- add-on to metformin + sulphonylurea

- add on to metformin and empagliflozin

- add-on to insulin with or without metformin

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

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

Table 1 Adverse reactions reported in patients who received linagliptin 5 mg daily as monotherapy or as add-on 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

Hypoglycaemia1

very common

Respiratory, thoracic and mediastinal disorders

Cough

uncommon

Gastrointestinal disorders

Pancreatitis

rare#

Constipation2

uncommon

Skin and subcutaneous tissue disorders

Angioedema*

rare

Urticaria*

rare

Rash*

uncommon

Bullous pemphigoid

rare#

Investigations

Amylase increased

uncommon

Lipase increased**

common

* Based on post-marketing experience

** Based on lipase elevations > 3 × ULN observed in clinical trials

# Based on Linagliptin cardiovascular and renal safety study (CARMELINA), see also below

1 Adverse reaction observed in combination with metformin plus sulphonylurea

2 Adverse reaction observed in combination with insulin

Linagliptin cardiovascular and renal safety study (CARMELINA)

The CARMELINA study evaluated the cardiovascular and renal safety of linagliptin versus placebo 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

Symptoms

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

Therapy

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.