INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LINATIN (LINATIN)

Composition:

Active substance: linagliptin;

One film-coated tablet contains 5 mg of linagliptin;

Excipients: mannite (E 421), pregelatinized starch, copovidone, crospovidone, magnesium stearate, Opadry Complete Coating System 03F250027 pink (hypromellose, titanium dioxide (E 171), polyethylene glycol, talc, iron oxide red (E 172)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: light red, round, convex film-coated tablets.

Pharmacotherapeutic group.

Medicinal products used in diabetes mellitus. Blood glucose lowering agents, excluding insulin. ATC code A10BH05.

Pharmacological Properties

Pharmacodynamics

Mechanism of action

Linagliptin is an inhibitor of the enzyme DPP-4 (dipeptidyl peptidase-4), an enzyme involved in the inactivation of incretin hormones GLP-1 and GIP (glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide). These hormones are rapidly degraded by the DPP-4 enzyme. Both incretin hormones participate in the physiological regulation of glucose homeostasis. Incretins are secreted at low basal levels throughout the day and their levels increase immediately after food intake. GLP-1 and GIP enhance insulin biosynthesis and secretion from pancreatic beta cells under conditions of normal or elevated blood glucose levels. In addition, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, leading to decreased hepatic glucose production. Linagliptin binds reversibly and with high affinity to DPP-4, thereby resulting in sustained elevation and prolongation of active incretin levels. Linagliptin increases insulin secretion and decreases glucagon secretion in a glucose-dependent manner, leading to overall improvement in glucose homeostasis. Linagliptin selectively binds to DPP-4 and shows more than 10,000-fold selectivity over DPP-8 or DPP-9 activity in vitro.

Clinical efficacy and safety

Eight phase III randomized controlled trials involving 5,239 patients with type 2 diabetes were conducted to evaluate the efficacy and safety of linagliptin, of whom 3,319 received treatment with linagliptin. A total of 929 patients aged 65 years or older received linagliptin. Additionally, 1,238 patients with mild renal impairment and 143 patients with moderate renal impairment were treated with linagliptin. Once-daily linagliptin resulted in clinically meaningful improvement in glycemic control without clinically significant change in body weight. Reduction in glycated hemoglobin A1c (HbA1c) was consistent across subgroups, including sex, age, renal function, and body mass index (BMI). A higher baseline HbA1c level was associated with greater HbA1c reduction. In pooled analyses, a significant difference in HbA1c reduction was observed between Asian patients (0.8%) and Caucasian patients (0.5%).

Linagliptin as monotherapy in patients unsuitable for metformin

The efficacy and safety of linagliptin monotherapy were evaluated in a double-blind, placebo-controlled 24-week study. Treatment with linagliptin 5 mg once daily provided a significant improvement in HbA1c levels (change of -0.69% vs placebo) in patients with a baseline HbA1c of approximately 8%. Linagliptin also demonstrated significant improvement in fasting plasma glucose and two-hour postprandial glucose (PPG) compared to placebo. The observed incidence of hypoglycemia in patients receiving linagliptin was similar to that with placebo.

In a double-blind, placebo-controlled 18-week study, the efficacy and safety of linagliptin monotherapy were also evaluated in patients for whom metformin therapy was inappropriate due to intolerance or contraindicated due to renal impairment. Linagliptin provided a significant improvement in HbA1c (change of -0.57% vs placebo) from a mean baseline HbA1c of 8.09%. Linagliptin also demonstrated significant improvement in fasting plasma glucose compared to placebo. The observed incidence of hypoglycemia in patients receiving linagliptin was similar to that with placebo.

Linagliptin as add-on therapy to metformin

The efficacy and safety of linagliptin in combination with metformin were evaluated in a double-blind, placebo-controlled 24-week study. Linagliptin provided a significant improvement in HbA1c levels (change of -0.64% vs placebo) from a mean baseline HbA1c of 8%. Linagliptin also demonstrated significant improvement in fasting plasma glucose and two-hour postprandial glucose (PPG) compared to placebo. The observed incidence of hypoglycemia in patients receiving linagliptin was similar to that with placebo.

Linagliptin as add-on therapy to combination therapy with metformin and sulfonylurea

A placebo-controlled 24-week study was conducted to evaluate the efficacy and safety of linagliptin 5 mg compared to placebo in patients inadequately controlled on combination therapy with metformin and sulfonylurea. Linagliptin provided a significant improvement in HbA1c (change of -0.62% vs placebo) from a mean baseline HbA1c of 8.14%. Linagliptin also demonstrated significant improvement in fasting plasma glucose and two-hour postprandial glucose (PPG) compared to placebo.

Linagliptin as add-on therapy to combination therapy with metformin and empagliflozin
In patients with inadequate control on metformin and empagliflozin (10 mg (n=247) or 25 mg (n=217)), 24-week treatment with additional therapy of linagliptin 5 mg resulted in an adjusted mean reduction in HbA1c from baseline of -0.53%. A statistically significant greater proportion of patients with baseline HbA1c ≥7% receiving 5 mg linagliptin achieved the target HbA1c <7% compared to placebo.

Linagliptin as add-on to insulin therapy

The efficacy and safety of adding 5 mg linagliptin to insulin alone or in combination with metformin and/or pioglitazone were evaluated in a double-blind, placebo-controlled 24-week study. Linagliptin provided a significant improvement in HbA1c (-0.65% vs placebo) from a mean baseline HbA1c of 8.3%. Linagliptin also provided significant improvement in fasting plasma glucose, and a greater proportion of patients achieved target HbA1c <7% compared to placebo. This was achieved with stable insulin dose (40.1 IU). Body weight did not differ significantly between groups. The effect on plasma lipids was minimal. The observed incidence of hypoglycemia in patients receiving linagliptin was similar to that with placebo (22.2% linagliptin; 21.2% placebo).

Data on linagliptin over 24 months as add-on to metformin compared with glimepiride

In a study comparing the efficacy and safety of adding 5 mg linagliptin or glimepiride (mean dose 3 mg) in patients with inadequate glycemic control on metformin monotherapy, mean reduction in HbA1c was -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 0.2% (97.5% CI: 0.09, 0.299). The incidence of hypoglycemia in the linagliptin group (7.5%) was significantly lower than in the glimepiride group (36.1%). Patients receiving linagliptin showed a significant mean reduction in body weight from baseline compared to a significant increase in body weight in patients receiving glimepiride (-1.39 vs +1.29 kg).

Linagliptin as add-on therapy in patients with severe renal impairment, 12-week placebo-controlled phase (stable background) and 40-week placebo-controlled extension phase (adjustable background)

The efficacy and safety of linagliptin were also evaluated in patients with type 2 diabetes and severe renal impairment in a double-blind, placebo-controlled 12-week study, during which background antidiabetic therapy was maintained stable. The majority of patients (80.5%) received insulin as background therapy alone or in combination with other oral antidiabetic agents such as sulfonylureas, glinides, or pioglitazone. An additional 40-week treatment period was included, during which dose adjustments of background antidiabetic therapy were allowed. Linagliptin provided a significant improvement in HbA1c (change of -0.59% vs placebo at 12 weeks) from a mean baseline HbA1c of 8.2%. The observed difference in HbA1c compared to placebo was -0.72% at 52 weeks.

Body weight did not differ significantly between groups. The observed incidence of hypoglycemia in patients receiving linagliptin was higher than with placebo, due to an increase in asymptomatic hypoglycemic events. There was no difference between groups in the incidence of severe hypoglycemic events.

Linagliptin as add-on therapy in elderly patients (age ≥70 years) with type 2 diabetes

The efficacy and safety of linagliptin in elderly patients (age ≥70 years) with type 2 diabetes were evaluated in a double-blind, 24-week study.

Patients received metformin and/or sulfonylurea and/or insulin as background therapy. Doses of background antidiabetic medications remained stable during the first 12 weeks, after which dose adjustments were allowed. Linagliptin provided a significant improvement in HbA1c (change of -0.64% vs placebo at 24 weeks) from a mean baseline HbA1c of 7.8%. Linagliptin also demonstrated significant improvement in fasting plasma glucose compared to placebo. Body weight did not differ significantly between groups.

Cardiovascular and renal safety trial of linagliptin (CARMELINA)

CARMELINA is a randomized trial involving 6,979 patients with type 2 diabetes and elevated cardiovascular risk, confirmed by history of established macrovascular or renal disease, who received 5 mg linagliptin (3,494) or placebo (3,485) added to standard of care, guided by regional standards for HbA1c, cardiovascular risk factors, and kidney disease. The study population included 1,211 (17.4%) patients aged ≥75 years and 4,348 (62.3%) patients with renal impairment. Approximately 19% of the population had eGFR from ≥45 to <60 mL/min/1.73 m², 28% had eGFR ≥30 to <45 mL/min/1.73 m², and 15% had eGFR <30 mL/min/1.73 m². Mean baseline HbA1c was 8.0%. The study was designed to demonstrate non-inferiority of the primary cardiovascular endpoint, defined as the composite of first occurrence of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke (3P-MACE). The renal composite endpoint was defined as renal death, persistent end-stage renal disease, or sustained reduction in eGFR by 40% or more. After a mean observation period of 2.2 years, linagliptin added to usual care did not increase the risk of serious cardiovascular events or renal outcomes. There was no increased risk of hospitalization for heart failure, an additional observed endpoint, compared to usual care without linagliptin in patients with type 2 diabetes (see table).

Cardiovascular and renal outcomes by treatment group in the CARMELINA study

Table 1

* PY = patient-years

** Non-inferiority test to demonstrate that the upper limit of the 95% CI for the risk ratio is less than 1.3.

In analyses of albuminuria progression (change from normoalbuminuria to micro- or macroalbuminuria, or from microalbuminuria to macroalbuminuria), the estimated risk ratio was 0.86 (95% CI 0.78, 0.95) for linagliptin compared with placebo.

Cardiovascular safety trial of linagliptin (CAROLINA).

CAROLINA is a randomized trial involving 6033 patients with early type 2 diabetes and either increased cardiovascular risk or established complications, who received treatment with either linagliptin 5 mg (3023 patients) or glimepiride 1–4 mg (3010 patients), added to standard therapy (including background metformin therapy in 83% of patients), targeting regional standards for HbA1c and cardiovascular risk factors. The mean age of the study population was 64 years, including 2030 (34%) patients aged ≥70 years. The study population included 2089 (35%) patients with cardiovascular disease and 1130 (19%) patients with impaired renal function and eGFR <60 mL/min/1.73 m² at baseline. Mean HbA1c at baseline was 7.15%. The trial was designed to demonstrate non-inferiority for the primary cardiovascular endpoint, which was a composite of first occurrence of cardiovascular death, non-fatal myocardial infarction (MI), or 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 below) compared with glimepiride. Results were consistent in patients who were receiving or not receiving metformin.

Major adverse cardiovascular events (MACE) and mortality by treatment group in the CAROLINA trial

Table 2

* PY = patient-years.

** Non-inferiority test to demonstrate that the upper limit of the 95% CI for the risk ratio is less than 1.3.

Over the entire treatment period (mean treatment duration 5.9 years), the incidence of patients with moderate or severe hypoglycemia was 6.5% on linagliptin versus 30.9% on glimepiride; severe hypoglycemia occurred in 0.3% of patients on linagliptin versus 2.2% on glimepiride. Pediatric patients.

The European Medicines Agency has deferred the obligation to submit the results of studies with linagliptin in one or more subsets of the pediatric population with type 2 diabetes (see section "Posology and method of administration" for information on use in pediatrics).

Pharmacokinetics.

The pharmacokinetics of linagliptin have been well characterized in healthy volunteers and patients with type 2 diabetes. After oral administration of a 5 mg dose to healthy volunteers or patients, linagliptin was rapidly absorbed, with maximum plasma concentration (mean Tmax) observed at 1.5 hours post-dose. The plasma concentration of linagliptin declined in a triphasic manner with a prolonged terminal half-life (terminal half-life of linagliptin exceeding 100 hours), which is primarily due to saturable, tight binding of linagliptin to DPP-4 and does not contribute to drug accumulation. The effective half-life for accumulation of linagliptin, determined after multiple oral doses of 5 mg linagliptin, is approximately 12 hours. Steady-state plasma concentrations are achieved after the third dose following administration of 5 mg linagliptin once daily. The AUC of linagliptin in plasma increased by approximately 33% at steady state after administration of a 5 mg dose compared to the first dose. Intra- and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Due to concentration-dependent binding of linagliptin to DPP-4, the pharmacokinetics of linagliptin based on total exposure are non-linear; indeed, total plasma AUC of linagliptin increases less than proportionally with dose, whereas AUC of unbound linagliptin increases approximately proportionally with dose. Pharmacokinetics of linagliptin were generally similar in healthy volunteers and patients with type 2 diabetes.

Absorption.

Absolute bioavailability of linagliptin is approximately 30%. Concomitant intake of a high-fat meal with linagliptin delayed the time to reach Cmax by 2 hours and reduced Cmax by 15%, but no effect on AUC from 0 to 72 hours was observed. No clinically significant effect of changes in Cmax and Tmax is expected; therefore, linagliptin can be taken independently of meals.

Distribution.

Due to tissue binding, the mean apparent volume of distribution at steady state after a single 5 mg intravenous dose of linagliptin to healthy volunteers is approximately 1110 liters, indicating extensive tissue distribution of linagliptin. Protein binding of linagliptin to plasma proteins is concentration-dependent and decreases from approximately 99% at 1 nmol/L to 75–89% at ≥ 30 nmol/L, reflecting saturation of DPP-4 binding as linagliptin concentration increases. At high concentrations, when DPP-4 is fully saturated, 70–80% of linagliptin binds to other plasma proteins rather than DPP-4, thus 30–20% remains unbound in plasma.

Biotransformation.

After oral administration of [14C] linagliptin at a dose of 10 mg, approximately 5% was excreted in urine. Metabolism plays a minor role in the elimination of linagliptin. One major metabolite was identified, with a relative linagliptin exposure of 13.3% at steady state, which was pharmacologically inactive and therefore did not contribute to DPP-4 inhibitory activity of linagliptin in plasma.

Elimination.

Following oral administration of a dose of [14C] linagliptin to healthy volunteers, approximately 85% of the administered radioactivity was excreted within 4 days after dosing, with 80% in feces and 5% in urine. Renal clearance at steady state was approximately 70 mL/min.

Special populations.

Renal impairment.

An open-label multiple-dose study was conducted to evaluate the pharmacokinetics of linagliptin (5 mg dose) in patients with varying degrees of chronic renal impairment compared to healthy control subjects. The study included patients with renal impairment classified based on 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. Additionally, patients with type 2 diabetes and severe renal impairment (< 30 mL/min) were compared to patients with type 2 diabetes and normal renal function. Creatinine clearance was measured via 24-hour urinary creatinine clearance or estimated from serum creatinine using the Cockcroft-Gault formula: CrCl = (140 – age) × body weight / (72 × serum creatinine) [× 0.85 for women], where age is in years, body weight in kg, and serum creatinine in mg/dL. At steady state, linagliptin exposure in patients with mild renal impairment was comparable to that in healthy volunteers. In moderate renal impairment, a moderate increase in exposure of approximately 1.7-fold was observed compared to controls. Exposure in patients with type 2 diabetes and severe renal impairment was increased by approximately 1.4-fold compared to patients with type 2 diabetes and normal renal function. Steady-state predictions for linagliptin AUC in patients with ESRD indicate comparable exposure to that in patients with moderate or severe renal impairment. Furthermore, linagliptin is not expected to be removed to a clinically significant extent by hemodialysis or peritoneal dialysis. Therefore, dose adjustment of linagliptin is not required in patients with any degree of renal impairment.

Hepatic impairment.

In non-diabetic patients with mild, moderate, and severe hepatic impairment (according to Child-Pugh classification), mean AUC and Cmax of linagliptin were similar to those in healthy subjects after multiple 5 mg doses of linagliptin. Dose adjustment of linagliptin is not recommended for patients with type 2 diabetes and mild, moderate, or severe hepatic impairment.

Body mass index (BMI).

Dose adjustment based on BMI is not required. BMI had no clinically significant effect on the pharmacokinetics of linagliptin based on population pharmacokinetic analysis of Phase I and Phase II data. Clinical trials conducted prior to marketing authorization included subjects with BMI up to 40 kg/m².

Gender.

Dose adjustment based on gender is not required. Gender had no clinically significant effect on the pharmacokinetics of linagliptin based on population pharmacokinetic analysis of Phase I and Phase II data.

Elderly patients.

Dose adjustment based on age up to 80 years is not required, as age had no clinically significant effect on the pharmacokinetics of linagliptin according to population pharmacokinetic analysis of Phase I and Phase II data. Elderly patients (aged 65 to 80 years, with the oldest patient being 78 years) had comparable plasma concentrations of linagliptin compared to younger subjects.

Pediatric population.

A Phase II pediatric study evaluated the pharmacokinetics and pharmacodynamics of 1 mg and 5 mg linagliptin in children and adolescents aged ≥ 10 to < 18 years with type 2 diabetes. Observed pharmacokinetic and pharmacodynamic values were consistent with those observed in adult patients. Linagliptin 5 mg showed superiority over 1 mg with regard to minimal DPP-4 inhibition (72% vs. 32%, p=0.0050) and numerically greater reduction in adjusted mean change in HbA1c from baseline (–0.63% vs. –0.48%). Due to the limited nature of the data set, results should be interpreted with caution.

Race.

Dose adjustment based on race is not required. According to a pooled analysis of available pharmacokinetic data, including Caucasian, Latino-American, African, and Asian race patients, race had no apparent effect on plasma concentrations of linagliptin. Furthermore, pharmacokinetic characteristics of linagliptin were found to be similar in dedicated Phase I studies involving healthy volunteers from Japan, China, and Caucasian populations.

Clinical Characteristics.

Indications.

The medicinal product is indicated for use in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control:

Monotherapy

• when metformin is inappropriate due to intolerance or contraindicated due to renal dysfunction;

Combination therapy

• in combination with other antidiabetic medicinal products, including insulin, when they do not provide adequate glycemic control.

Contraindications.

Hypersensitivity to the medicinal product or to any of its components.

Interaction with other medicinal products and other forms of interaction.

Evaluation of in vitro interactions

Linagliptin is a weak competitive inhibitor of the CYP3A4 isoenzyme, but does not inhibit other CYP isoenzymes. It is not an inducer of CYP isoenzymes. Linagliptin is a substrate of P-glycoprotein and weakly inhibits P-glycoprotein-mediated digoxin transport. Based on in vivo interaction study results, it is unlikely that linagliptin will cause interactions with other P-gp substrates.

Evaluation of in vivo interactions.

Effect of other medicinal products on linagliptin.

The data described below indicate a low risk of clinically significant interactions with concomitantly administered medicinal products.

Rifampicin: repeated co-administration of 5 mg linagliptin with rifampicin, a potent inducer of P-glycoprotein and CYP3A4, resulted in a reduction of linagliptin AUC and Cmax at steady state by 39.6% and 43.8%, respectively, and approximately a 30% reduction in DPP-4 inhibition. Therefore, full efficacy of linagliptin in combination with strong P-gp inducers may not be achieved, especially if administered long-term. Concomitant use 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 oral 5 mg dose of linagliptin with multiple oral doses of ritonavir 200 mg, a potent inhibitor of P-glycoprotein and CYP3A4, increased the AUC and Cmax of linagliptin by approximately two-fold and three-fold, respectively. Unbound concentrations, typically less than 1% at therapeutic doses of linagliptin, increased 4–5 fold after co-administration with ritonavir. Modeling of plasma concentration-time profiles of linagliptin with and without ritonavir showed that the increased exposure would not be associated with increased accumulation. These changes in the pharmacokinetics of linagliptin are not considered clinically significant. Therefore, no clinically relevant interaction is expected with other inhibitors of P-glycoprotein/CYP3A4.

Metformin: repeated co-administration of 850 mg metformin three times daily with 10 mg linagliptin once daily did not result in clinically significant changes in the pharmacokinetics of linagliptin in healthy volunteers.

Sulfonylurea derivatives: steady-state pharmacokinetics of 5 mg linagliptin were not altered by co-administration of a single 1.75 mg dose of glyburide (glibenclamide).

Effect of linagliptin on other medicinal products.

In clinical studies, as described below, linagliptin had no clinically significant effect on the pharmacokinetics of metformin, glyburide, simvastatin, warfarin, digoxin, or oral contraceptives, providing in vivo evidence of low potential for drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cation transporter (OCT). Metformin: repeated co-administration of multiple daily doses of 10 mg linagliptin with 850 mg metformin, an OCT substrate, had no significant effect on the pharmacokinetics of metformin in healthy volunteers. Thus, linagliptin is not an inhibitor of OCT-mediated transport.

Sulfonylurea derivatives: repeated oral doses of 5 mg linagliptin co-administered with a single oral dose of 1.75 mg glyburide (glibenclamide) resulted in a clinically insignificant reduction in AUC and Cmax of glyburide by 14%. Since glyburide is predominantly metabolized by CYP2C9, these data also support the conclusion that linagliptin is not an inhibitor of CYP2C9. Clinically significant interactions are not expected with other sulfonylurea derivatives (e.g., glipizide, tolbutamide, and glimepiride), which, like glyburide, are primarily eliminated via CYP2C9.

Digoxin: repeated daily doses of 5 mg linagliptin co-administered with multiple 0.25 mg doses of digoxin had no effect on digoxin pharmacokinetics in healthy volunteers. Thus, 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 as a single dose.

Simvastatin: multiple daily doses of linagliptin had minimal effect on the steady-state pharmacokinetics of simvastatin, a sensitive CYP3A4 substrate, in healthy volunteers. After administration of a supratherapeutic dose of 10 mg linagliptin co-administered with 40 mg simvastatin daily for 6 days, plasma AUC of simvastatin increased by 34% and plasma Cmax by 10%.

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

Special precautions for use.

General.

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

Hypoglycemia.

The incidence of hypoglycemia with linagliptin was comparable to placebo. In clinical trials of linagliptin as part of combination therapy with antidiabetic medicinal products known to cause hypoglycemia (metformin), the reported incidence of hypoglycemia with linagliptin was similar to that in patients receiving placebo. When linagliptin was added to sulfonylureas (on a background of metformin), the incidence of hypoglycemia increased compared to placebo (see section "Adverse reactions").

Sulfonylureas and insulin are known to cause hypoglycemia. Therefore, caution should be exercised when using linagliptin in combination with sulfonylureas and/or insulin. Consideration may be given to reducing the dose of sulfonylurea or insulin (see section "Dosage and administration").

Acute pancreatitis.

Use of DPP-4 inhibitors has been associated with a risk of acute pancreatitis. Cases of acute pancreatitis have been observed in patients treated with linagliptin. In the cardiovascular and renal safety study (CARMELINA), with a median observation period of 2.2 years, acute pancreatitis was reported in 0.3% of patients receiving linagliptin and in 0.1% of patients receiving placebo. Patients should be informed about the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, the medicinal product should be discontinued; if acute pancreatitis is confirmed, the drug should not be restarted. Caution is advised 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 receiving linagliptin treatment and in none of the patients receiving placebo. If bullous pemphigoid is suspected, treatment with the medicinal product should be discontinued.

Use during pregnancy or breastfeeding.

Pregnancy.

The use of linagliptin in pregnant women has not been studied. Animal studies do not indicate a direct or indirect harmful effect on reproductive toxicity. Use of linagliptin during pregnancy is not recommended.

Period of breastfeeding.

Available data confirm that linagliptin and its metabolites pass into animal milk. Risk to the breastfed infant cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from linagliptin therapy, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility.

Studies on the effect of linagliptin on human fertility have not been conducted. Animal studies do not indicate a direct or indirect harmful effect on fertility.

Ability to affect reaction speed when driving or operating machinery.

Linagliptin has no effect or a negligible effect on the ability to drive or operate machinery. However, patients should be warned about the risk of hypoglycemia, particularly when used in combination with sulfonylureas and/or insulin.

Method of administration and dosage.

Dosage.

The dose of linagliptin is 5 mg once daily.

When adding linagliptin to metformin, the dose of metformin should not be changed, and linagliptin should be administered concomitantly.

When using linagliptin in combination with a sulfonylurea or insulin, to reduce the risk of hypoglycemia, it is recommended to reduce the dose of the sulfonylurea or insulin (see section "Special instructions").

Special patient groups.

Renal impairment.

Dose adjustment of linagliptin is not required in patients with renal impairment.

Hepatic impairment.

Pharmacokinetic studies indicate that dose adjustment is not required in patients with hepatic impairment; however, there is no clinical experience in treating such patients.

Elderly patients.

Dose adjustment based on age is not required.

Pediatric patients.

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

Method of administration.

Tablets can be taken independently of food intake at any time of 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.

Children.

To date, there is insufficient experience with the use of linagliptin in children and adolescents. Therefore, the medicinal product is not prescribed to this age group of patients.

Overdose.

Symptoms. In controlled clinical studies in healthy volunteers, single doses of up to 600 mg of linagliptin (equivalent to 120 times the recommended dose) were generally well tolerated. There is no experience with doses exceeding 600 mg in humans.

Treatment. In case of overdose, standard supportive measures are recommended, for example, removal of the unabsorbed drug from the gastrointestinal tract (gastric lavage), monitoring of the patient's clinical status, and, if necessary, immediate therapeutic interventions should be initiated.

Adverse reactions.

Summary of safety profile

In a pooled analysis of placebo-controlled studies, the overall incidence of adverse reactions was similar in patients receiving placebo compared to linagliptin 5 mg (63.4% vs. 59.1%). Discontinuation of treatment due to adverse events was higher in patients receiving placebo compared to those receiving linagliptin 5 mg (4.3% vs. 3.4%).

The most commonly reported adverse reaction was "hypoglycemia," observed with the triple combination of linagliptin + metformin + sulfonylurea in 14.8% vs. 7.6% with placebo.

In placebo-controlled studies, "hypoglycemia" occurred as an adverse reaction in 4.9% of patients treated with linagliptin. Of these, 4% were mild, 0.9% were moderate, and 0.1% were classified as severe in intensity. Pancreatitis was reported more frequently in patients randomized to linagliptin (7 events in 6580 patients receiving linagliptin vs. 2 events in 4383 patients receiving placebo).

Tabulated list of adverse reactions

Due to the influence of background therapy on adverse reactions (e.g., on hypoglycemia), adverse reactions were analyzed based on relevant treatment regimens (monotherapy, add-on to metformin, add-on to metformin plus sulfonylurea, and add-on to insulin). Placebo-controlled studies included trials in which linagliptin was administered as:

• short-term monotherapy up to 4 weeks,
• monotherapy for ≥12 weeks,
• add-on to metformin,
• add-on to metformin + sulfonylurea,
• add-on to metformin and empagliflozin,
• add-on to insulin with or without metformin.

The table below lists adverse reactions classified by system organ classes and preferred MedDRA terms in patients receiving linagliptin 5 mg in double-blind studies as monotherapy or as add-on therapy.

All adverse reactions are listed by system organ class and frequency: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Adverse reactions observed in patients receiving linagliptin 5 mg once daily as monotherapy or as add-on therapy during clinical studies and post-marketing experience.

* Based on post-marketing experience.

** Based on increase in lipase > 3xULN observed in clinical trials.

Based on the Cardiovascular and Renal Evaluation of Linagliptin (CARMELINA) study, see below.

1 Adverse reaction observed in combination with metformin plus sulfonylurea.

2 Adverse reaction observed in combination with insulin.

Cardiovascular and Renal Safety Study of Linagliptin (CARMELINA).

The CARMELINA study evaluated the cardiovascular and renal safety of linagliptin compared to placebo in patients with type 2 diabetes and increased cardiovascular risk, confirmed by documented history of macrovascular or renal disease (see section "Pharmacodynamics"). The study included 3494 patients receiving linagliptin (5 mg) and 3485 patients receiving placebo. Both treatments were added to standard of care tailored to regional standards for HbA1c and cardiovascular 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 obtained in this study were consistent with the previously known safety profile of linagliptin. Among patients receiving treatment, severe hypoglycaemic events (requiring assistance) occurred in 3% of patients receiving linagliptin and in 3.1% of patients receiving placebo. Among patients using sulfonylurea at study initiation, the incidence of severe hypoglycaemia was 2% in patients receiving linagliptin and 1.7% in those receiving placebo. Among patients using insulin at baseline, the incidence of severe hypoglycaemia was 4.4% in patients receiving linagliptin and 4.9% in those receiving placebo.

During the overall observation period, suspected acute pancreatitis was reported in 0.3% of patients receiving linagliptin and in 0.1% of patients receiving placebo.

In the CARMELINA study, bullous pemphigoid was reported in 0.2% of patients receiving linagliptin and in none of the patients receiving placebo.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, as well as patients or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach and sight of children.

Packaging.

30 tablets in a blister pack, 1 blister pack in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

NOBEL ILAC SANAYI VE TICARET A.S.

Manufacturer's address and location of operations.

Sankaklar District, Eskikaraçay Street No:299, 81100 Düzce, Turkey.