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).

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
The safety and efficacy of linagliptin in children and adolescents has not yet been established. No data
are available.
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.

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.

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 coadministered
medicinal products is low.
Rifampicin: multiple co-administration of 5 mg linagliptin with rifampicin, a potent inductor of Pglycoprotein
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.

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 breastfeeding
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).

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.

Summary of the safety profile
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

* 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 3494 patients treated with linagliptin
(5 mg) and 3485 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.
Reporting of suspected adverse reactions
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222,
Ext: 2317-2356-2340.
o Reporting hotline: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc
• Other GCC States:
− Please contact the relevant competent authority.

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.

Pharmacotherapeutic group: Drugs used in diabetes, dipeptidyl peptidase 4 (DPP-4) inhibitors.
ATC code: A10BH05
Mechanism of action
Linagliptin is an inhibitor of the enzyme DPP-4 (dipeptidyl peptidase 4, EC 3.4.14.5) an enzyme which is
involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide1, glucosedependent
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.
Clinical efficacy and safety
8 phase III randomised controlled trials involving 5,239 patients with type 2 diabetes, of which 3,319
were treated with linagliptin were conducted to evaluate efficacy and safety. These studies had 929
patients of 65 years and over who were on linagliptin. There were also 1,238 patients with mild renal
impairment, and 143 patients with moderate renal impairment on linagliptin. Linagliptin once daily
produced clinically significant improvements in glycaemic control, with no clinically relevant change in
body weight. The reductions in glycosylated haemoglobin A1c (HbA1c) were similar across different
subgroups including gender, age, renal impairment and body mass index (BMI). Higher baseline
HbA1c was associated with a greater reduction in HbA1c. There was a significant difference in reduction
in HbA1c between Asian patients (0.8%) and White patients (0.5%) in the pooled studies.
Linagliptin as monotherapy in patients ineligible for metformin
The efficacy and safety of linagliptin monotherapy was evaluated in a double-blind placebo-controlled
study of 24 weeks duration. Treatment with once daily linagliptin at 5 mg provided a significant
improvement in HbA1c (-0.69% change compared to placebo), in patients with baseline HbA1c of
approximately 8%. Linagliptin also showed significant improvements in fasting plasma glucose (FPG),
and 2-hour post-prandial glucose (PPG) compared to placebo. The observed incidence of hypoglycaemia
in patients treated with linagliptin was similar to placebo.
The efficacy and safety of linagliptin monotherapy was also evaluated in patients for whom metformin
therapy is inappropriate, due to intolerability or contraindicated due to renal impairment, in a doubleblind
placebo-controlled study of 18 weeks duration. Linagliptin provided significant improvements in
HbA1c, (-0.57% change compared to placebo), from a mean baseline HbA1c of 8.09%. Linagliptin also
showed significant improvements in fasting plasma glucose (FPG) compared to placebo. The observed
incidence of hypoglycaemia in patients treated with linagliptin was similar to placebo.

Linagliptin as add-on to metformin therapy
The efficacy and safety of linagliptin in combination with metformin was evaluated in a double-blind
placebo-controlled study of 24 weeks duration. Linagliptin provided significant improvements in HbA1c,
(-0.64% change compared to placebo), from a mean baseline HbA1c of 8%. Linagliptin also showed
significant improvements in fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG)
compared to placebo. The observed incidence of hypoglycaemia in patients treated with linagliptin was
similar to placebo.
Linagliptin as add-on to a combination of metformin and sulphonylurea therapy
A placebo-controlled study of 24 weeks in duration was conducted to evaluate the efficacy and 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 fasting plasma glucose (FPG), and 2-hour post-prandial glucose (PPG), compared to placebo.
Linagliptin as add-on to a combination of metformin and empagliflozin therapy
In patients inadequately controlled with metformin and empagliflozin (10 mg (n=247) or 25 mg (n=217)),
24-weeks treatment with add-on therapy of linagliptin 5 mg provided adjusted mean 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 as add-on to insulin therapy
The efficacy and safety of the addition of linagliptin 5 mg to insulin alone or in combination with
metformin and/or pioglitazone has been evaluated in a double-blind placebo-controlled study of 24 weeks
duration. Linagliptin provided significant improvements in HbA1c (-0.65% compared to placebo) from a
mean baseline HbA1c of 8.3%. Linagliptin also provided significant improvements in fasting plasma
glucose (FPG), and a greater proportion of patients achieved a target HbA1c of < 7.0%, compared to
placebo. This was achieved with a stable insulin dose (40.1 IU). Body weight did not differ significantly
between the groups. Effects on plasma lipids were negligible. The observed incidence of hypoglycaemia
in patients treated with linagliptin was similar to placebo (22.2% linagliptin; 21.2% placebo).
Linagliptin 24 month data, as add-on to metformin in comparison with glimepiride
In a study comparing the efficacy and safety of the addition of linagliptin 5 mg or glimepiride (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
vs +1.29 kg).
Linagliptin as add-on therapy in patients with severe renal impairment, 12 week placebo-controlled data
(stable background) and 40 week placebo-controlled extension (adjustable background)

The efficacy and safety of linagliptin was also evaluated in type 2 diabetes patients with severe renal
impairment in a double-blind study versus placebo for 12 weeks duration, during which background
glycaemic therapies were kept stable. Most patients (80.5%) received insulin as background therapy,
alone or in combination with other oral anti-diabetics such as sulphonylurea, glinide and pioglitazone.
There was a further follow up 40 week treatment period during which dose adjustments in antidiabetes
background therapies were allowed.
Linagliptin provided significant improvements in HbA1c (-0.59 % change compared to placebo after 12
weeks), from a mean baseline HbA1c of 8.2%. The observed difference in HbA1c over placebo was -
0.72% after 52 weeks.
Body weight did not differ significantly between the groups. The observed incidence of hypoglycaemia
in patients treated with linagliptin was higher than placebo, due to an increase in asymptomatic
hypoglycaemic events. There was no difference between groups in severe hypoglycaemic events.
Linagliptin as add-on therapy in elderly (age ≥ 70 years) with type 2 diabetes
The efficacy and safety of linagliptin in elderly (age ≥ 70years) 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 antidiabetic medicinal products 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.
Linagliptin cardiovascular and renal safety study (CARMELINA)
CARMELINA was a randomized study in 6979 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 (3494) or placebo (3485) added to standard of care targeting regional standards for HbA1c, CV risk
factors and renal disease. The study population included 1211 (17.4%) patients ≥ 75 years of age and
4348 (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 usual 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
usual care without linagliptin in patients with type 2 diabetes (see table 2).
Table 2 Cardiovascular and renal outcomes by treatment group in the CARMELINA study

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

* 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- or macroalbuminuria, or from microalbuminuria to macroalbuminuria) the estimated hazard ratio was 0.86 (95% CI 0.78, 0.95) for linagliptin versus placebo.

Linagliptin cardiovascular safety study (CAROLINA)
CAROLINA was a randomized study in 6033 patients with early type 2 diabetes and increased CV risk
or established complications who were treated with linagliptin 5 mg (3023) or glimepiride 1-4mg (3010)
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 was 64 years and
included 2030 (34%) patients ≥ 70 years of age. The study population included 2089 (35%) patients with
cardiovascular disease and 1130 (19%) patients with renal impairment with an eGFR <
60ml/min/1.73m2 at baseline. The mean HbA1c at baseline was 7.15%.
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).

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

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

* 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 moderate or severe hypoglycaemia was 6.5% on linagliptin versus 30.9% on glimepiride, severe hypoglycaemia occurred in 0.3% of patients on linagliptin versus 2.2% on glimepiride.

Paediatric population

The clinical efficacy and safety of empagliflozin 10 mg with potential dose-increase to 25 mg or linagliptin 5 mg once daily has been studied in children and adolescents from 10 to 17 years of age with T2DM in a double-blind, randomised, placebo-controlled, parallel group study (DINAMO) over 26 weeks, with a double-blind active treatment safety extension period up to 52 weeks.

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

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 medicinal product. The effective
half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of 5 mg
linagliptin, is approximately 12 hours. After once daily dosing of 5 mg linagliptin, steady-state plasma concentrations are reached by the third dose. Plasma AUC of linagliptin increased approximately 33%
following 5 mg doses at steady-state compared to the first dose. The intra-subject and inter-subject
coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Due to the
concentration dependent binding of linagliptin to DPP-4, the pharmacokinetics of linagliptin based on
total exposure is not linear; indeed total plasma AUC of linagliptin increased in a less than doseproportional
manner while unbound AUC increases in a roughly dose-proportional manner. The
pharmacokinetics of linagliptin was generally similar in healthy subjects and in patients with type 2
diabetes.
Absorption
The absolute bioavailability of linagliptin is approximately 30%. Co-administration of a high-fat meal
with linagliptin prolonged the time to reach Cmax by 2 hours and lowered Cmax by 15% but no influence
on AUC 0-72h was observed. No clinically relevant effect of Cmax and Tmax changes is expected; therefore
linagliptin may be administered with or without food.
Distribution
As a result of tissue binding, the mean apparent volume of distribution at steady-state following a single
5 mg intravenous dose of linagliptin to healthy subjects is approximately 1,110 litres, indicating that
linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentrationdependent,
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 high concentrations, where DPP-4 is
fully saturated, 70-80% of linagliptin was bound to other plasma proteins than DPP-4, hence 30-20%
were unbound in plasma.
Biotransformation
Following a [14C] linagliptin oral 10 mg dose, approximately 5% of the radioactivity was excreted in
urine. Metabolism plays a subordinate role in the elimination of linagliptin. One main metabolite with a
relative exposure of 13.3% of linagliptin at steady-state was detected which was found to be
pharmacologically inactive and thus does not contribute to the plasma DPP-4 inhibitory activity of
linagliptin.
Excretion
Following administration of an oral [14C] linagliptin dose to healthy subjects, approximately 85% of the
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.
Special populations
Renal impairment
A multiple-dose, open-label study was conducted to evaluate the pharmacokinetics of linagliptin (5 mg
dose) in patients with varying degrees of chronic renal insufficiency compared to normal healthy control
subjects. The study included patients with renal insufficiency classified on the basis of creatinine
clearance as mild (50 to <80 ml/min), moderate (30 to <50 ml/min), and severe (<30 ml/min), as well as
patients with ESRD on hemodialysis. In addition patients with T2DM and severe renal impairment (<30 ml/min) were compared to T2DM patients with normal renal function. Creatinine clearance was
measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine
based on the Cockcroft-Gault formula. CrCl = (140 – age) x weight/72 x serum creatinine [x 0.85 for
females], where age is in years, weight in kg, and serum creatinine is in mg/dl. Under steady-state
conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy
subjects. In moderate renal impairment, a moderate increase in exposure of about 1.7 fold was observed
compared with control. Exposure in T2DM patients with severe RI was increased by about 1.4 fold
compared to T2DM patients with normal renal function. Steady-state predictions for AUC of linagliptin
in patients with ESRD indicated comparable exposure to that of patients with moderate or severe renal
impairment. In addition, linagliptin is not expected to be eliminated to a therapeutically significant degree
by hemodialysis or peritoneal dialysis. Therefore, no dosage adjustment of linagliptin is necessary in
patients with any degree of renal insufficiency.
Hepatic impairment
In non-diabetic patients with mild moderate and severe hepatic insufficiency (according to the Child-
Pugh classification), mean AUC and Cmax of linagliptin were similar to healthy matched controls
following administration of multiple 5 mg doses of linagliptin. No dosage adjustment for linagliptin is
proposed for diabetic patients with mild, moderate or severe hepatic impairment.
Body Mass Index (BMI)
No dosage adjustment is necessary based on BMI. BMI had no clinically relevant effect on the
pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II
data. The clinical trials before marketing authorisation have been performed up to a BMI equal to 40
kg/m2.
Gender
No dosage adjustment is necessary based on gender. Gender had no clinically relevant effect on the
pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II
data.
Elderly
No dosage adjustment is required based on age up to 80 years, as age did not have a clinically relevant
impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I
and Phase II data. Older subjects (65 to 80, oldest patient was 78 years) had comparable plasma
concentrations of linagliptin compared to younger subjects.
Paediatric population
A paediatric Phase 2 study examined the pharmacokinetics and pharmacodynamics of 1 mg and 5 mg
linagliptin in children and adolescents ≥10 to <18 years of age with type 2 diabetes mellitus. The
observed pharmacokinetic and pharmacodynamic responses were consistent with those found in adult
subjects. 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 from baseline in
HbA1c (-0.63% vs -0.48%, n.s.). Due to the limited nature of the data set the results should be interpreted
cautiously.

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

Liver, kidneys and gastrointestinal tract are the principal target organs of toxicity in mice and rats at
repeat 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 than 1,500
times human exposure. Strong pseudo-allergic reactions were observed in dogs at medium doses,
secondarily causing cardiovascular changes, which were considered dog-specific. Liver, kidneys,
stomach, reproductive organs, thymus, spleen, and lymph nodes were target organs of toxicity in
Cynomolgus monkeys at more than 450 times human exposure. At more than 100 times human 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 or
male mice. A significantly higher incidence of malignant lymphomas only in female mice at the highest
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 no concern 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 in rats was 49
times human exposure. No teratogenic effects were observed in rabbits at >1,000 times human exposure.
A NOAEL of 78 times human exposure was derived for embryo-fetal toxicity in rabbits, and for maternal
toxicity the NOAEL was 2.1 times human exposure. Therefore, it is considered unlikely that linagliptin
affects reproduction at therapeutic exposures in humans.

Mannitol
Pregelatinised Starch-1500
Maize Starch
Kollidon VA 64 (Copovidone)
Magnesium Stearate
Opadry white-03B28796
Iron Oxide Red
Talc

Not applicable

Do not store above 30° C.

Alu-Alu Blister.
3 blister pack (3 x 10’s Tablets)

No special requirements.