Trajenta: Antidiabetic drug independent with renal function

2021-06-27 06:38 AM

Trajenta is indicated for the treatment of type 2 diabetes mellitus (T2DM) in adult patients to improve glycemic control, glycemic control monotherapy, or in combination with metformin, with pioglitazone or a sulfonylurea, with insulin.

Producer

Boehringer Ingelheim

Ingredient

Each tablet: Linagliptin 5mg.

Describe

Oblique, biconvex, round, light red film-coated tablets, embossed with the Boehringer Ingelheim company logo on one side and the letter “D5” on the other.

Pharmacodynamic properties

Pharmacotherapeutic group: DPP-4 inhibitors, ATC code: A10BH05.

Linagliptin is an inhibitor of the enzyme DPP-4 (Dipeptidyl peptidase 4, EC 3.4.14.5), which is involved in the inactivation of the incretin hormones GLP-1 and GIP (glucagon-like peptide-1, a secondary insulin-stimulating polypeptide) belonging to glucose). These hormones are usually rapidly degraded by the enzyme DPP-4. Both incretin hormones are involved in the physiological regulation of glucose homeostasis. Incretin is excreted at a low concentration throughout the day and this concentration increases immediately after ingestion. GLP-1 and GIP promote insulin synthesis and secretion from pancreatic beta-cells under normal and hyperglycemic conditions. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in decreased hepatic glucose secretion. Linagliptin (Trajenta) binds very efficiently to DPP-4 and can be dissociated thereby increasing stable and prolonged concentrations of active incretin. Trajenta increases glucose-dependent insulin secretion and decreases glucagon secretion thereby generally improving glucose homeostasis. Linagliptin binds selectively to DPP-4 and is >10,000-fold selective for DPP-8 or DPP-9 activity in vitro.

Clinical trials

Linagliptin monotherapy for patients unable to take metformin

The efficacy and safety of linagliptin monotherapy were also evaluated in patients for whom metformin therapy was inappropriate, because of intolerance or contraindication in an 18-year double-blind placebo-controlled study. weeks, then extended safety monitoring to 34 weeks (placebo-treated patients switched to glimepiride). Linagliptin significantly improved HbA1c, (0.60% reduction compared to placebo), from the baseline mean HbA1c value of 8.09%. The mean change in HbA1c from baseline remained unchanged in the linagliptin group from week 18 to week 52. Linagliptin also showed a significant improvement in fasting plasma glucose (FPG) (20.5 mg/dL (decreased by 20.5 mg/dL). 1.1 mmol/L (equivalent to 1.1 mmol/L) versus placebo) and a large proportion of patients achieved target HbA1c <7.0% compared with placebo. The incidence of hypoglycaemia observed in patients treated with linagliptin was similar to placebo and lower than in the glimepiride group during the extended safety monitoring period. Bodyweight did not differ significantly between groups during the 18 weeks of placebo control, and patients treated with glimepiride experienced an increase in body weight during extended safety monitoring.

Linagliptin as an adjunct to metformin therapy

The efficacy and safety of linagliptin in combination with metformin were evaluated in a double-blind, placebo-controlled study of 24 weeks duration. Linagliptin significantly improved HbA1c, (-0.64% vs placebo), from baseline mean HbA1c 8%. Linagliptin also showed a significant improvement in fasting plasma glucose (FPG) (21.1 mg/dL (1.2 mmol/L, respectively), and 2-hour postprandial blood sugar (PPG) reduction by 67,1 mg/dL (3.7 mmol/L, respectively) compared with placebo and the proportion of patients achieving target HbA1c <7.0% (28.3% in the linagliptin group vs 11.4% in the linagliptin group vs. The incidence of hypoglycaemia observed in patients treated with linagliptin was similar to that of a placebo, and body weight did not differ significantly between the groups.

The efficacy and safety of linagliptin in combination with metformin at baseline were evaluated in a 24-week placebo-controlled factorial study. Linagliptin 2.5 mg twice daily in combination with metformin (500 mg or 1000 mg twice daily) showed significant improvement in glycemic parameters compared with the monotherapy groups (baseline mean HbA1c 8,65 %. The mean HbA1c difference between linagliptin + metformin vs metformin monotherapy from baseline through week 24 (based on final assessment results – abbreviated LOCF) was 0.51 reduction. % (95% CI -0.73, -0.30; p<0.0001) for linagliptin 2.5mg + metformin 1000 mg twice daily compared with metformin 1000 mg twice daily, a reduction of 0, 58% (95% CI -0.79, -0.36; p<0.0001) for linagliptin 2.5 mg + metformin 500 mg twice daily compared with metformin 500 mg twice daily. The mean change in HbA1c in the placebo-adjusted group from baseline for linagliptin 2.5 mg/metformin 1000 mg twice daily was 1.71% leading to HbA1c control (<7.0). %) in 53.6% of patients (compared to 30.7% of patients treated with metformin 1000 mg twice daily as monotherapy). Mean HbA1c reductions from initiation of treatment were generally greater in patients with higher baseline HbA1c values. 

Effects on plasma lipids are generally absent. Bodyweight loss with the combination of linagliptin and metformin was similar to that of metformin monotherapy or placebo; There were no changes from baseline in patients receiving linagliptin alone. The incidence of hypoglycemia was similar between the treatment groups (placebo 1.4%, linagliptin 5 mg 0%, metformin 2.1%, and linagliptin 2.5 mg with metformin twice daily 1.4%).

In addition, this study included patients (n=66) with more severe hyperglycemia (HbA1c at baseline ≥11%) and who received twice-daily open-label treatment with linagliptin 2, 5 mg and metformin 1000 mg. In this group of patients, the mean HbA1c value at baseline was 11.8% and the mean FPG was 261.8 mg/dL (14.5 mmol/L, respectively). Mean HbA1c reductions from baseline of 3.74% (n=48) and 81.2 mg/dL (4.5 mmol/L, respectively) reductions in FPG (n=41) were observed in these patients. patients completed a 24-week clinical trial with no rescue treatment. In the LOCF analysis that included all patients with the primary endpoint as measured at last follow-up (n=65) without salvage therapy, the change from baseline was a 3.19% reduction for HbA1c and decreased by 73.6% mg/dL (corresponding to 4.1 mmol/L) for FPG.

The efficacy and safety of linagliptin 2.5 mg twice daily compared with 5 mg once daily in combination with metformin in patients not adequately glycemic control with metformin monotherapy were evaluated in one study. 12-week double-blind, placebo-controlled study. Linagliptin (2.5 mg twice daily and 5 mg once daily) added to metformin significantly improved glycemic parameters compared with placebo. Linagliptin 5 mg once daily and 2.5 mg twice daily significantly reduced HbA1c to a similar extent (CI: -0.07; 0.19), by 0.80% (compared to baseline 7, 98%), and a decrease of 0.74 (from baseline 7.96%) compared with placebo. The incidence of hypoglycaemia observed in patients treated with linagliptin was similar to that of placebo. Bodyweight did not differ significantly between the groups.

Linagliptin as an adjunct to sulphonylurea therapy

The efficacy and safety of linagliptin in combination with sulphonylurea were evaluated in an 18-week, double-blind, placebo-controlled study. Linagliptin significantly improved HbA1c, (0.47% reduction compared to placebo), from a baseline HbA1c value of 8.6%. Linagliptin also showed a significant improvement in the percentage of patients achieving a target HbA1c <7.0%. Bodyweight did not differ significantly between the groups.

Linagliptin as an addition to insulin therapy

The efficacy and safety of adding 5 mg of linagliptin to insulin as monotherapy or in combination with metformin and/or pioglitazone were evaluated in a double-blind, placebo-controlled study of 24 weeks duration. The treatment mean difference in HbA1c between linagliptin and placebo at baseline through week 24 (analysis based on final values) was reduced by 0.65% (95% CI - 0.74, -0.55; p<0.0001) compared with the mean HbA1c value at baseline 8.3%. The mean reduction from baseline HbA1c was greater in general for patients with higher baseline HbA1c. The mean HbA1c change from baseline was maintained in the linagliptin group from weeks 12 to 24. Linagliptin also showed a significant improvement in fasting glucose (FPG) of 11.25 mg/dL. (0.62 mmol/L, respectively) (95% CI, -16.14, -6.36; p<0.0001) compared with placebo, and the proportion of patients achieving target HbA1c <7.0 % higher than placebo. This result is achieved with a steady dose of insulin.

The mean daily insulin dose at baseline was 42 units in linagliptin-treated patients and 40 units in placebo-treated patients. The mean change in daily insulin dose from baseline through week 24 was 1.3 units in the placebo group and 0.6 units in the linagliptin treatment group. Bodyweight did not differ significantly between the groups. No effect on plasma lipids. The incidence of hypoglycemia was similar between the treatment groups (22.2% linagliptin; 21.2% placebo).

Linagliptin as an adjunct to combination therapy with metformin and a sulphonylurea

A 24-week placebo-controlled study was conducted to evaluate the efficacy and safety of linagliptin 5 mg compared with placebo, in patients not adequately treated with metformin plus a sulphonylurea. Linagliptin resulted in a significant improvement in HbA1c (0.62% reduction compared to placebo), from a mean baseline HbA1c of 8.14%. Linagliptin also showed a significant improvement in the percentage of patients achieving a target HbA1c <7.0%, and a reduction in fasting plasma glucose (FPG) by 12.7 mg/dL (0.7 mmol/L, respectively). ) compared with placebo. Bodyweight was not significantly different between the treatment groups.

Linagliptin as an add-on to metformin and empagliflozin combination therapy

In patients inadequately controlled with metformin and empagliflozin (10 mg (n=247) or 25 mg (n=217)), 24 weeks of treatment with linagliptin 5 mg add-on therapy resulted in a significant reduction in mean HbA1c. Adjusted for baseline mean HbA1c was 0.53% (significant difference from placebo of 0.32% (95% CI -0.25; -0.13), and 0.58%, respectively. significantly different from placebo was 0.47% (95% CI -0.66; -0.28) Proportion of patients with baseline mean HbA1c value ≥7.0% and treated with linagliptin 5 mg achieved a target HbA1c (<7%) that was statistically significantly higher than placebo.

In predefined subgroups of patients with baseline HbA1c values ​​≥8.5% (number of patients on metformin and empagliflozin 10 mg or 25 mg, n=66 and n=42, respectively) , mean HbA1c decreased from baseline HbA1c after 24 weeks of treatment with linagliptin 5 mg add-on therapy was 0.97% (p=0.0875, difference from placebo) and 1, 16% (p=0.0046, different from placebo).

Linagliptin for initial combination therapy with pioglitazone

In a 24-week placebo-controlled study of linagliptin 5 mg plus pioglitazone (30 mg) at the outset, the combination of linagliptin and pioglitazone significantly improved HbA1c compared with pioglitazone and placebo (reduction of 0,51%), from the mean baseline HbA1c value of 8.6%. The initial combination of linagliptin and pioglitazone also significantly improved fasting plasma glucose (FPG) (14.2 mg/dL (0.8 mmol/L) compared with placebo), and incidence patients can achieve target HbA1c (<7%), and HbA1c reduction ≥of 0.5% is also higher. Bodyweight was significantly increased with the combination of linagliptin and pioglitazone compared with pioglitazone and placebo (1.1 kg).

Linagliptin as an add-on to combination therapy with metformin and pioglitazone

A 24-week controlled study evaluated the safety and efficacy of linagliptin 5 mg compared with placebo in patients not controlled with the combination of metformin and pioglitazone. Linagliptin resulted in a significant improvement in HbA1c (0.57% reduction compared to placebo), from a mean baseline HbA1c value of 8.42%.

Linagliptin also showed significant improvement in patients who achieved a target HbA1c <7.0%, and also reduced fasting blood glucose (FPG) (10.4 mg/dL/0.6 mmol/L) compared with placebo. Bodyweight did not differ between the groups.

24-month data for linagliptin added to metformin and comparison with glimepiride

In a study comparing the efficacy and safety of the addition of linagliptin 5 mg or glimepiride (a sulphonylurea) in patients not adequately controlled on metformin alone, linagliptin was similar to glimepiride in decreased HbA1c, with a mean treatment difference of HbA1c from baseline to week 104 for linagliptin compared with glimepiride increasing by 0.20%. In this study, the pro-insulin to insulin ratio, which represents the efficiency of insulin synthesis and release, showed a statistically significant improvement with linagliptin compared with glimepiride treatment. The rate of hypoglycemia was significantly lower in the linagliptin group (7.5%) than in the glimepiride group (36.1%). Patients treated with linagliptin lost a significant mean weight loss from baseline, while significant weight gain was observed 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 (stable treatment) and 40-week placebo-controlled (adjustable) extended period data.

The efficacy and safety of linagliptin were also evaluated in type 2 diabetic patients with severe renal impairment in a 12-week double-blind study versus placebo, during which prior antidiabetic treatment is kept stable. The patients were previously treated with various therapies including insulin, sulphonylurea, glinides, and pioglitazone. There is a 40-week follow-up period during which the initial dose of antidiabetic agents can be adjusted.

Linagliptin significantly improved HbA1c (0.59% change versus placebo), from a mean baseline HbA1c value of 8.2%. A higher percentage of patients achieved a target HbA1c <7.0% compared with placebo. The difference in HbA1c observed compared with placebo decreased by 0.72% after 52 weeks.

Bodyweight did not differ significantly between the groups. The incidence of hypoglycaemia was higher in patients treated with linagliptin than in the placebo, due to an increased incidence of asymptomatic hypoglycaemic events. This can be caused by available diabetes treatments (insulin and sulphonylurea or glinides). There were no intergroup differences in serious 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 with type 2 diabetes mellitus (age ≥70 years) were evaluated in a double-blind placebo-controlled study of 24 weeks duration. At study entry, the patient was being treated with metformin and/or sulphonylurea and/or insulin. Doses of available antidiabetic agents were stabilized for the first 12 weeks, after which dose adjustments were allowed. Linagliptin significantly improved HbA1c, reducing 0.64% (95% CI -0.81, -0.48; p<0.0001) compared with placebo after 24 weeks, calculated from the mean HbA1c value. the initial rate was 7.8%. Linagliptin also significantly improved fasting blood glucose (FPG) by 20.7 mg/dL (1.1 mmol/L) (95% CI -30.2, -11.2; p<0.0001) compared with placebo. Bodyweight did not differ significantly between the groups. The proportion of patients with hypoglycaemia was also compared on the basis of existing treatment with insulin with or without metformin (13 of 35 patients, 37.1% treated with linagliptin, and 6 of 15 patients, respectively). 40% of the placebo treatment). However, against a background of preexisting sulphonylurea with or without metformin, a higher proportion of hypoglycaemia was reported in the linaliptin group (24 of 82 patients, 29.3%). ) compared with placebo (7 of 42 patients, 16.7%). There were no group differences in serious hypoglycemic events.

Linagliptin is an addition  to prior therapy with oral antidiabetic agents for more than 52 weeks in Japanese type 2 diabetic patients

The safety and efficacy of linagliptin have been evaluated in an open-label, parallel-group study in Japanese type 2 diabetic patients inadequately controlled with an oral antidiabetic agent. biguanide, glinide, glitazone, sulphonylurea [SU] or α-glucosidase inhibitor [A-GI]).

Linagliptin significantly improved HbA1c and FPG from baseline at week 52 for all previously treated groups, from a mean baseline HbA1c of 7.98%. The range is down from 0.70% to 0.91%. Improvement was observed with a reduction of 0.88% in the biguanide and linagliptin groups; 0.73% reduction in glinide and linagliptin groups; 0.79% reduction in glitazone and linagliptin groups; 0.70% reduction in sulphonylurea and linagliptin groups; and 0.91% reduction in the group of α-glucosidase inhibitors and linagliptin. For FPG, the range drops from 6.0 mg/dL/0.3 mmol/L and 12.6 mmol/dL/0.7 mmol/L. The reduction observed was 12.6 mmol/dL/0.7 mmol/L in the biguanide and linagliptin groups; 9.1 mmol/dL/0.5 mmol/L in the glinide and linagliptin groups; 9.8 mmol/dL/0.5 mmol/L in the glitazone and linagliptin groups; 6.7 mmol/dL/0.4 mmol/L in the sulphonylurea and linagliptin groups; and 6.0 mg/dL/0.3 mmol/L in the α-glucosidase inhibitors and linagliptin groups. Bodyweight changes were not significant from baseline until week 52 in all previously treated groups.

Linagliptin reduced HbA1c similarly to metformin when added to existing treatment with a sulphonylurea, with a mean HbA1c difference from baseline to week 52 of 0.18% in the linagliptin group compared with metformin.

Linagliptin reduced HbA1c similarly to metformin when added to existing α-glucosidase inhibitor therapy, with a mean HbA1c difference from baseline to week 52 of 0.09% in the linagliptin group compared with metformin.

Hypoglycaemic events were reported infrequently and of mild severity in all groups (5.8%) except in patients pre-treated with a sulphonylurea. The incidence of hypoglycemia was mainly observed when linagliptin was administered with a sulphonylurea (81%); however, this frequency was similar for metformin in patients already on sulphonylurea therapy.

Initiation of treatment with a combination of linagliptin and metformin in a newly diagnosed and drug-naive patient with significant hyperglycemia

Efficacy and safety of initiating treatment with a combination of linagliptin 5 mg once daily and metformin twice daily (adjusted during the first 6 weeks to 1500 mg or 2000 mg/day) compared with linagliptin 5 mg once daily times daily was studied in a 24-week trial in newly diagnosed type 2 diabetes mellitus patients with significant and drug-naive hyperglycemia (baseline HbA1c 8.5-12.0%) ). After 24 weeks, both the linagliptin monotherapy regimens and the initiation of the combination linagliptin and metformin significantly reduced HbA1c levels by 2% and 2.8%, respectively, compared with baseline mean HbA1c values ​​of 9.9 % and 9.8%. The treatment difference was reduced by 0.8% (95% CI -1.1 to -0.5) indicating that initiation of combination therapy was superior to monotherapy (p<0.0001). In particular, 40% and 61% of patients in the monotherapy and combination arm achieved HbA1c <7%.

Cardiovascular risk

In a prospective meta-analysis of independently evaluated cardiovascular events from 19 clinical studies (lasting 18 to 24 months) in 9459 patients with type 2 diabetes, Treatment with linagliptin was not associated with an increased cardiovascular risk.

The primary endpoint consisted of a composite of events: occurrence or time to cardiovascular death, the first occurrence of nonfatal myocardial infarction, nonfatal stroke, or hospitalization for pain. unstable angina, which was not significantly lower with linagliptin compared with either the active comparator or placebo [hazard ratio 0.78 (95% CI 0.55; 1.12)] . A total of 60 major events in the linagliptin group and 62 major events in the comparator arm. Cardiovascular events were observed at a similar rate between the linagliptin and placebo groups (hazard ratio 1.09 (95% CI 0.68; 1.75)]. with placebo, a total of 43 major events (1.03%) in the linagliptin group and 29 major events (1.35%) in the placebo group.

Child object

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

Pharmacokinetic properties

The pharmacokinetics of linagliptin has been extensively described in healthy subjects and in patients with type 2 diabetes. Following oral administration of 5 mg to healthy volunteers or patients, linagliptin was rapidly absorbed with peak concentrations in the plasma. plasma (median Tmax) appeared 1.5 hours after administration.

Plasma concentrations of linagliptin decrease in a minimal 2 phases with a long elimination half-life (terminal half-life of linagliptin longer than 100 hours), which is almost entirely related to the saturating state, linagliptin binds tightly to DPP-4 and does not contribute to its accumulation. The cumulative effective half-life of linagliptin was determined after multiple oral doses of 5 mg linagliptin, approximately 12 hours. Following a single daily dose, steady-state plasma concentrations of linagliptin 5 mg were achieved after the third dose. The plasma AUC of linagliptin increased by approximately 33% following the administration of 5 mg doses in steady-state relative to the first dose. The intra- and inter-patient coefficients of variation for linagliptin AUC were small (12.6% and 28.5%), respectively. Plasma AUC of linagliptin increased less than dose proportionally. The pharmacokinetics of linagliptin are generally comparable in healthy subjects and in patients with type 2 diabetes.

Absorb

The absolute bioavailability of linagliptin is approximately 30%. Administration of linagliptin with a high-fat meal has no clinically relevant effect on the pharmacokinetics, linagliptin may be administered with or without food. In vitro studies indicate that linagliptin is a substrate of P-glycoprotein and CYP3A4. Ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4 resulting in a 2-fold increase in exposure (AUC), and repeated administration of linagliptin with rifampicin, a strong inducer of P-gp and CYP3A, resulting in a decrease in approximately 40% of the AUC of linagliptin was at steady state, presumably due to increased/decreased bioavailability of linagliptin by inhibition/induction of P-glycoprotein.

Distribution

Due to tissue binding, the mean steady-state volume of distribution following a single 5 mg intravenous dose of linagliptin in healthy subjects was approximately 1110 liters, indicating that linagliptin is widely distributed to tissues. The plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at concentrations of 1 nmol/L to 75-89% at concentrations ≥30 nmol/L, reflecting saturation of binding to DPP-4 at concentrations of 30 nmol/L. increased levels of linagliptin. At high concentrations, when DPP-4 is completely saturated, 70-80% of linagliptin is bound to plasma proteins other than DPP-4, thus 20-30% is unbound in plasma.

Metabolism

Following a single dose of [14C] linagliptin 10 mg orally, approximately 5% of the radioactivity was excreted in the urine. Metabolism plays a secondary role in the elimination of linagliptin. A major metabolite with a relative concentration of 13.3% of a steady-state dose of linagliptin was found to be pharmacologically inactive and therefore does not contribute to the plasma DPP-4 inhibitory activity of linagliptin. linagliptin.

Excrete

Following oral administration of [14C] linagliptin to healthy subjects, approximately 85% of a radioactive dose was excreted in feces (80%) or urine (5%) within 4 days of dosing. The steady-state renal clearance is about 70 mL/min.

Special patient group

Renal failure

An open-label, the multiple-dose study was conducted to evaluate the pharmacokinetics of linagliptin (5 mg dose) in patients with varying degrees of chronic renal failure compared with healthy controls. The study included patients with an impaired renal function who were classified based on creatinine clearance as mild (50 to <80 mL/min), moderate (30 to <50 mL/min), and severe (<30 mL/min). /min), as well as patients with end-stage renal disease (ESRD) on dialysis. In addition, patients with type 2 diabetes and severe renal impairment (<30 mL/min) were compared with patients with type 2 diabetes with normal renal function. Creatinine clearance was calculated by measuring 24-hour urinary creatinine clearance or estimated from serum creatinine using the Cockcroft-Gault formula:

CrCL = [140 – age (years)] x body weight (kg) {x 0.85 for female patients} / [72 x serum creatinine (mg/dL)].

At a steady state, linagliptin concentrations in patients with mild renal impairment are comparable to those in healthy subjects. In cases of moderate renal impairment, there was a moderate increase in concentrations of approximately 1.7-fold compared with controls. Concentrations in type 2 diabetic patients with severe renal impairment were approximately 1.4 times higher than in type 2 diabetic patients with normal renal function. The predicted steady-state AUC of linagliptin in patients with ESRD end-stage renal disease showed exposure concentrations similar to those in patients with moderate or severe renal impairment. In addition, linagliptin is less likely to be removed to a significant extent by hemodialysis or peritoneal dialysis. Therefore, no dose adjustment of linagliptin is necessary for patients with any degree of renal impairment. In addition, mild renal impairment had no effect on the pharmacokinetics of linagliptin in patients with type 2 diabetes as assessed by population pharmacokinetic analysis.

Liver failure

In patients with mild-moderate and severe hepatic impairment (according to the Child-Pugh classification), mean AUC and Cmax of linagliptin were similar to those of healthy matched controls after multiple doses of 5 mg of linagliptin. No dose adjustment of linagliptin is necessary for patients with mild, moderate, or severe hepatic impairment.

Body mass index (BMI)

It is not necessary to adjust the dose based on BMI. Body mass index has no clinical relevance to the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of phase I and phases II data.

Sex

It is not necessary to adjust the dose 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 dose adjustment based on age is necessary, as age is not clinically relevant to the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of phase I and phase II data. Elderly subjects (65 to 80 years of age) have similar plasma linagliptin concentrations to younger subjects.

Children

Studies to determine the pharmacokinetics of linagliptin in pediatric patients have not been performed.

Race

It is not necessary to adjust the dose based on ethnicity. The race had no significant effect on plasma concentrations of linagliptin based on a meta-analysis of available pharmacokinetic data, including Caucasian, Hispanic, African-American, and Caucasian patients. Asia. In addition, the pharmacokinetics of linagliptin were observed to be similar to those observed in specific phase I studies in healthy Japanese, Chinese and Caucasian volunteers and patients with type 2 diabetes. African American.

Indications and uses

Trajenta is indicated for the treatment of type 2 diabetes mellitus (T2DM) in adult patients to improve glycemic control:

Monotherapy

The patient has not had good glycemic control with diet and exercise and the patient is not suitable for treatment with metformin due to intolerance or contraindication due to renal failure.

Combination therapy

In combination with metformin when diet and exercise together with metformin monotherapy do not provide good glycemic control;

In combination with pioglitazone or sulfonylurea when monotherapy does not control blood sugar well;

Combination with metformin + sulfonylurea or metformin + sodium-glucose co-transporter 2 inhibitor (SGLT2 inhibitor) (triple treatment regimen) when two-drug regimen does not provide good glycemic control.

Combination with insulin with or without metformin, when this insulin regimen in combination with diet and exercise does not provide good glycemic control.

Trajenta is not indicated in patients with type 1 diabetes or in diabetic patients with ketoacidosis.

Dosage and Administration

Adults

The recommended dosage is 5 mg once daily. Trajenta can be taken with or without food at any time of the day. When linagliptin is combined with a sulphonylurea, a lower dose of sulphonylurea may be considered to reduce the risk of hypoglycemia.

Renal failure

No dose adjustment is required in patients with renal impairment.

Liver failure

No dose adjustment is required in patients with hepatic impairment.

Elderly

No dose adjustment is necessary.

Children and adolescents

The use of Trajenta in children under 18 years of age is not recommended due to a lack of data on safety and efficacy.

Missed dose

If a dose is missed, it should be taken again as soon as the patient remembers. Do not take a double dose on the same day.

Warning

Generality

Trajenta should not be used in patients with type 1 diabetes or in patients with diabetic ketoacidosis.

Hypoglycemia

Linagliptin monotherapy showed rates of hypoglycaemia comparable to placebo.

In clinical trials with linagliptin as part of combination therapy with non-hypoglycemic agents (metformin), the incidence of hypoglycaemia reported with linagliptin was comparable to placebo.

When linagliptin was used in combination with sulphonylurea (on the background of metformin), the incidence of hypoglycaemia was increased compared with placebo.

Sulphonylureas and insulin are known to cause hypoglycemia. Therefore, caution should be exercised when linagliptin is used in combination with sulphonylurea and/or insulin. A reduction in the dose of sulphonylurea or insulin may be considered.

Acute pancreatitis

The use of DPP-4 inhibitors is associated with an increased risk of developing acute pancreatitis. There have been spontaneous reports of acute pancreatitis adverse events from post-marketing experience with linagliptin. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Trajenta should be discontinued; If acute pancreatitis is confirmed, treatment with Trajenta should not be initiated. Caution should be exercised in patients with a history of pancreatitis.

Bullous pemphigoid

There have been post-marketing reports of pemphigoid bullae in patients receiving linagliptin. If bullous pemphigoid is suspected, Trajenta should be discontinued.

Effects of the drug on the ability to drive and use machines

No studies have been conducted on the ability to drive and use machines.

Overdose

Symptom

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

Treatment

In cases of overdose, the usual supportive measures should be taken, eg removal of unabsorbed drug from the gastrointestinal tract; Clinical monitoring, and application of treatment measures if necessary.

Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Use in pregnant and lactating women

Pregnancy

There are limited data on the use of linagliptin in pregnant women. Animal studies have not shown a direct or indirect harmful effect on toxicity on fertility. As a precaution, it is better to avoid using Trajenta during pregnancy.

Breastfeeding

Available pharmacodynamic/toxicological data in animals indicate excretion of linagliptin/metabolites in human milk.

It is not known whether the drug is excreted in human milk. Therefore, caution should be exercised when Trajenta is used in lactating women.

Fertility

No human fertility studies have been conducted with Trajenta. No adverse effects on fertility were observed in animals up to a maximum dose of 240 mg/kg/day (approximately 943 times the human dose based on AUC comparisons).

Pharmacokinetic interactions

Evaluation of drug interactions in vitro

Linagliptin is a weak to moderate mechanism-based and weakly competitive inhibitor of CYP isozyme CYP3A4 but does not inhibit other CYP isozymes. The drug is not an inducer of CYP isozymes.

Linagliptin is a P-glycoprotein substrate and inhibits P-glycoprotein-mediated digoxin transport with low potency. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to interact with other P-gp substrates.

Evaluation of drug interactions in vivo

The clinical data described below suggest that the risk of clinically significant interactions from concomitant drug use is low. No clinically important interactions requiring dose adjustment have been observed. Linagliptin did not have a clinically significant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin, or oral contraceptives, which provides in vivo evidence of a tendency towards less interaction. Drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cation transporter (OCT).

Metformin: In healthy volunteers, co-administration of metformin 850 mg three times daily with a dose above the therapeutic threshold of 10 mg linagliptin once daily did not produce clinically significant changes in the pharmacokinetics of linagliptin or metformin. Therefore, linagliptin is not an inhibitor of OCT-mediated transport.

Sulphonylurea: The steady-state pharmacokinetics of 5 mg linagliptin were not altered by a single 1.75 mg dose of glibenclamide (glyburide) and multiple 5 mg oral doses of linagliptin. However, there was a 14% decrease in both AUC and Cmax values ​​of glibenclamide which was not clinically significant. Since glibenclamide is metabolized primarily by CYP2C9, these data also support that linagliptin is not an inhibitor of CYP2C9. Clinically significant interactions are unlikely with other sulphonylureas (eg, glipizide, tolbutamide, and glimepiride) that are eliminated primarily by CYP2C9 in the same way as glibenclamide.

Thiazolidinedione: Co-administration of multiple daily doses of 10 mg linagliptin (above the therapeutic threshold) with multiple 45 mg daily doses of pioglitazone, a CYP2C8, and CYP3A4 substrate, had no clinically significant effect on the pharmacokinetics of either linagliptin or pioglitazone or the active metabolite of pioglitazone, which indicates that linagliptin is not an inhibitor of CYP2C8-mediated metabolism in vivo and supports the conclusion that the inhibitory effect of linagliptin on CYP3A4 in vivo is trivial.

Ritonavir: A study was conducted to evaluate the effect of ritonavir, a potent inhibitor of P-glycoprotein and CYP3A4, on the pharmacokinetics of linagliptin. Co-administration of a single oral dose of 5 mg linagliptin and multiple oral doses of 200 mg ritonavir resulted in a 2-fold and 3-fold increase in AUC and Cmax of linagliptin, respectively. Simulation of steady-state plasma linagliptin concentrations with and without ritonavir showed that increases in drug concentrations were not associated with increased accumulation. These changes in the pharmacokinetics of linagliptin are not expected to be clinically significant.

Therefore, clinically significant interactions are unlikely with other P-glycoprotein/CYP3A4 inhibitors and no dose adjustment is necessary.

Rifampicin: A study was conducted to evaluate the effect of rifampicin, a potent inducer of P-glycoprotein and CYP3A4, on the pharmacokinetics of linagliptin when administered at a dose of 5 mg. Co-administration of multiple doses of linagliptin with rifampicin resulted in 39.6% and 43.8% reductions in linagliptin AUC and Cmax and approximately 30% reduction in DPP-4 inhibition at trough concentrations. Therefore, linagliptin when combined with a potent inducer of P-gp may be clinically effective, although the full effect may not be achieved.

Digoxin: Co-administration of multiple daily doses of linagliptin 5 mg 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 linagliptin 5 mg did not alter the pharmacokinetics of S(-) or R(+) warfarin, a CYP2C9 substrate, which indicates that linagliptin is not an inhibitor of CYP2C9.

Simvastatin: Multiple daily doses of linagliptin 10 mg (above the therapeutic threshold) had minimal effect on the steady-state pharmacokinetics of simvastatin, a sensitive CYP3A4 substrate, in healthy volunteers. Following concomitant administration of 10 mg of linagliptin with 40 mg of simvastatin daily for 6 days, plasma AUC of simvastatin increased by 34% and plasma Cmax by 10%. Therefore, linagliptin is considered to be a weak inhibitor of CYP3A4-mediated metabolism, and dosage adjustment of co-administered drugs metabolized by CYP3A4 is considered unnecessary.

Oral contraceptives: Concomitant administration of 5 mg of linagliptin did not alter the steady-state pharmacokinetics of levonorgestrel or ethiylestradiol.

The absolute bioavailability of linagliptin is approximately 30%. Since co-administration of linagliptin with a high-fat meal has no clinically relevant effect on the pharmacokinetics, linagliptin can be administered with or without food.

Side effects

The safety of Trajenta has been evaluated in patients with type 2 diabetes, most of whom received the target dose of 5 mg.

In a meta-analysis of placebo-controlled clinical studies, the overall incidence of adverse events in placebo-treated patients was similar to that of linagliptin 5 mg (63.4%) compared to 59.1%).

Discontinuation due to adverse events was observed higher in the placebo group than in the linagliptin 5 mg group (4.3% vs 3.4%).

Due to the influence of the initial treatment available on adverse events (eg, hypoglycemia), adverse events were analyzed and presented based on the respective regimens (monotherapy, adjuvant therapy). adjunct to metformin, add to thiazolidinedione (PPARγ) therapy), add to sulphonylurea therapy, add to metformin and sulphonylurea therapy, to insulin therapy, and to treatment with metformin and an SGLT2 inhibitor.

Placebo-controlled studies included 28 studies in which linagliptin was used as:

Short-term monotherapy for up to 4 weeks.

Monotherapy ≥ 12 weeks.

Add to metformin.

Initial combination therapy with pioglitazone.

In addition to sulphonylurea.

Add to metformin + sulphonylurea.

Addition to insulin (with or without metformin and/or pioglitazone and/or a sulphonylurea).

Add to therapy with metformin and empagliflozin.

Adverse reactions classified by the terms SOC and MedDRA were reported in patients receiving 5 mg of Trajenta in 18 double-blind studies as monotherapy, in combination with first-line therapy, or as treatment. adjuvant therapy presented for each regimen.

Adverse events are listed in absolute frequency. The frequencies were identified as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1 /1000 to <1/1000), or very rare (<1/10000), and unknown (cannot be estimated from the available data).

The safety of the combination linagliptin+metformin+pioglitazone was evaluated in 183 patients. The safety profile was similar to the established safety profile of linagliptin, linagliptin+metformin, and linagliptin+pioglitazone.

The most frequently reported adverse events of hypoglycaemia observed after triple combination therapy of linagliptin, metformin, and sulphonylurea were 22.9% compared with 14.8% in the placebo group.

Hypoglycemia in placebo-controlled studies (10.9%; N=471) was mild (80%; N=384) or moderate (16.6%; N=78) or severe (1.9 %; N=9).

Side effects noted from post-marketing experience

From post-marketing experience the following undesirable effects have been reported:

Preservation

Store no more than 30°C.

Presentation and packaging

Film-coated tablets: Box of 3 blisters x 10 tablets.