Trajenta Duo: A combination antidiabetic drug

2021-06-27 06:06 AM

Trajenta Duo is indicated for the treatment of type 2 diabetes mellitus and should be treated concomitantly with linagliptin and metformin. Trajenta Duo is indicated in combination with a sulphonylurea (ie a 3-drug regimen) along with an appropriate regimen.

Producer

Boehringer Ingelheim.

Ingredient

Each tablet: Linagliptin 2.5mg, metformin 500mg, or

Each tablet: Linagliptin 2.5mg, metformin 850mg, or

Each tablet: Linagliptin 2.5mg, metformin 1000mg.

Pharmacological

Treatment subgroup: Combination of oral hypoglycemic agents, ATC code: A10BD11

Linagliptin is an inhibitor of the DPP-4 enzyme (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, insulin-dependent insulin-stimulating polypeptide). glucose). These hormones are 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 increase insulin biosynthesis and glucagon secretion from pancreatic beta cells when blood glucose is normal and elevated. Furthermore, GLP-1 also reduces glucagon secretion from pancreatic alpha cells, resulting in decreased hepatic glucose secretion. Linagliptin binds very efficiently to DPP-4 and can be dissociated, thereby stably increasing and prolonging the concentration of active incretin. Linagliptin 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.

Metformin hydrochloride is an antihyperglycemic biguanide, which reduces both basal and postprandial plasma glucose concentrations. The drug does not stimulate insulin secretion, so it does not cause hypoglycemia.

Metformin hydrochloride may act through 3 mechanisms:

(1) reduces hepatic glucose production by inhibiting glucose synthesis and glycogenolysis

(2) In muscle, by increasing insulin sensitivity, it improves peripheral glucose absorption and utilization

(3) and slows down the absorption of glucose in the intestine.

Metformin hydrochloride stimulates intracellular glycogen synthesis by acting on glycogen synthase.

Metformin hydrochloride increases the transport capacity of all known transmembrane glucose transporters (GLUTs).

In humans, metformin hydrochloride also has a favorable effect on lipid metabolism, independent of its glycemic effect. This effect was observed at therapeutic doses in controlled clinical studies of medium and long duration: metformin hydrochloride reduces total cholesterol, LDL cholesterol and triglycerides.

Clinical trials

Linagliptin as an adjunct to metformin therapy

The efficacy and safety of linagliptin in combination with metformin in patients not glycemic control with metformin monotherapy were evaluated in a double-blind, placebo-controlled study of 24 weeks duration. Linagliptin in combination with metformin significantly improved HbA1c (-0.64% change compared to placebo) from a baseline HbA1c value of 8%.

Linagliptin also showed a significant improvement in fasting plasma glucose (FPG) with a reduction of 21.1 mg/dL (1.2 mmol/L) and a 2-hour postprandial glucose (PPG) reduction of 67.1 mg /dL (3.7 mmol/L) compared with placebo and a higher percentage of patients achieving a target HbA1c < 7.0% (28.3% in the linagliptin group vs 11.4% in the placebo group). The incidence of hypoglycemia observed in patients treated with linagliptin was similar to that of placebo. Body mass did not differ significantly between the groups.

In a 24-week, a placebo-controlled factorial study evaluating initial therapy, linagliptin 2.5 mg twice daily in combination with metformin (500 mg or 1000 mg twice daily) significantly improved glycemic-related parameters compared with monotherapy (mean baseline HbA1c 8.65%).

The mean decrease in HbA1c from baseline was generally greater in patients with higher baseline HbA1c values. Effects on plasma lipids are generally absent. Weight 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). Mean reductions from baseline in HbA1c of 3.74% (n=48) and 81.2 mg/dL (4.5 mmol/L) for FPG (n=41) were observed in completed patients. All clinical trials lasted 24 weeks with no lifesaving treatment. In the LOCF analysis that included all patients with identified primary endpoint (n=65) at last follow-up without salvage therapy, the change from baseline was a 3.19% reduction for HbA1c decreased by 73.6% mg/dL (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 a 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 the same extent as placebo (CI: -0.17; 0.19), a reduction of 0.80% (vs. initial 7.98%, and 0.74% (compared to baseline 7.96%). The incidence of hypoglycemia observed in patients treated with linagliptin was comparable to that of placebo (2.2% with linagliptin 2.5 mg twice daily, 0.9% with linagliptin 5 mg once daily). and 2.3% with placebo). Body mass did not differ significantly between the groups.

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 well controlled on metformin plus a sulphonylurea. Linagliptin significantly improved HbA1c (0.62% reduction compared to placebo) from the baseline mean HbA1c value of 8.14%.

Linagliptin also showed a significant improvement in the percentage of patients achieving a target HbA1c < 7.0% (31.2% in the linagliptin group vs 9.2% in the placebo group) and fasting plasma glucose (FPG). ) with a reduction of 12.7 mg/dL (0.7 mmol/L) compared with placebo. Body mass did not differ significantly between the treatment groups.

Linagliptin in combination with metformin and insulin

A 24-week, placebo-controlled study was conducted to evaluate the safety and efficacy of linagliptin (5 mg once daily) in addition to insulin therapy with or without metformin. 83% of patients were taking metformin in combination with insulin in this study. Linaglipin in combination with metformin plus insulin showed a significant improvement in HbA1c in this subgroup with the mean corrected from baseline decreasing by 0.68% (CI: -0.78; -0.57) (value). mean baseline HbA1c was 8.28%) compared with placebo when combined with metformin plus insulin. There was no significant change in body weight from baseline in both groups.

24-month data for linagliptin as an add-on to metformin regimens compared with glimepiride

In a study comparing the safety and efficacy 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 a reduction in HbA1c, with the mean HbA1c treatment difference from baseline to week 104 for linagliptin versus glimepiride of +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 significant mean weight from baseline, while patients receiving glimepiride gained significant weight (-1.39 vs +1.29 kg).

Linagliptin supports the treatment in elderly patients with type 2 diabetes (age ≥70 years)

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. Overall, rates of hypoglycaemia were similar between the linagliptin group (2 of 45 patients, 4.4%) and placebo (0 of 22 patients, 0%) on the background of metformin monotherapy. 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 linagliptin group (24 of 82 patients, 29.3%). ) compared with placebo (7 of 42 patients, 16.7%). There was no difference between the linagliptin and placebo groups in terms of serious hypoglycaemic events.

In a meta-analysis in elderly (age ≥70 years) type 2 diabetic patients (n=183) who were already receiving metformin and basal insulin, linagliptin in combination with metformin and insulin significantly improved HbA1c with an effective Mean correction from baseline was reduced by 0.81 (CI: -1.01, -0.61) (mean baseline HbA1c 8.13%) compared with placebo plus metformin plus insulin. There was no clinically significant difference in the rate of hypoglycaemic events in patients ≥70 years of age (37.2 in the linagliptin plus metformin plus insulin group vs 39.8% in the placebo ended group). combination of metformin and insulin).

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 linagliptin monotherapy and initiating the combination of linagliptin and metformin significantly reduced HbA1c levels by 2% and 2.8%, respectively, from baseline HbA1c values ​​of 9.9% and 2.8%, respectively. 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 therapy arms achieved HbA1c <7%.

Cardiovascular risk

In a meta-analysis, prospective, independently evaluated cardiovascular events from 19 clinical studies in 9459 patients with type 2 diabetes, treatment with linagliptin were not associated with an increased cardiovascular risk.

The primary endpoint, including a combination of occurrence or time to occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina, was not significantly lower with linagliptin compared with controls, active and 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 controls.

Cardiovascular events were observed at a similar rate between the linagliptin and placebo groups [hazard ratio 1.09 (95% CI 0.68; 1.75)]. In the placebo-controlled studies, a total of 43 major events (1.03%) in the linagliptin group and 29 major events (1.35%) in the placebo group.

Pharmacokinetics

Bioequivalence studies conducted in healthy volunteers have shown that Trajenta Duo (linagliptin/metformin hydrochloride) combination tablets are bioequivalent to the combination of linagliptin and metformin hydrochloride alone.

Administration of Trajenta Duo 2.5/1000mg with food did not change the overall concentration of linagliptin. Metformin AUC was unchanged; however, peak metformin serum concentrations were reduced by 18% when co-administered with food. The time to peak serum metformin concentration was delayed by 2 hours when co-administered with food. These changes are less likely to be clinically important.

The statements below reflect the pharmacokinetics of the individual active ingredients in Trajenta Duo.

Linagliptin

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, linagliptin was rapidly absorbed with peak concentrations in the plasma. plasma (median Tmax) appeared 1.5 hours after administration.

The plasma linagliptin concentrations of linagliptin decrease in two phases with a long half-life (the elimination half-life of linagliptin is 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, as determined after multiple oral doses of 5 mg linagliptin, is 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 was increased by approximately 33% following steady-state 5 mg doses compared with the first dose. The intra- and inter-patient coefficients of variation for linagliptin AUC were small (12.6% and 28.5%), respectively.

The plasma AUC of linagliptin increased less than the 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 about 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 strong inhibitor of P-glycoprotein and CYP3A4 resulted in a 2-fold increase in drug exposure (AUC), and multiple co-administration of linagliptin with rifampicin, a strong inducer of P-gp and CYP3A, resulted in a reduction of approximately 40 % of linagliptin AUC concentration at steady state, probably due to increased/decreased bioavailability of linagliptin by inhibition/induction of P-glycoprotein.

Distribution

Due to tissue binding, the mean apparent volume of distribution at steady state following a single 5 mg intravenous dose of linagliptin in healthy subjects is approximately 1110 liters, indicating that linagliptin is widely distributed to tissues. . 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 with increased linagliptin concentrations. At high concentrations, when DPP-4 is completely saturated, 70-80% of linagliptin is bound to plasma proteins other than DPP-4, thus 30-20% 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.

Elimination

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.

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 impaired renal function 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). /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 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 the control group.

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 end-stage renal disease ESRD showed drug concentrations similar to those in patients with moderate or severe renal impairment.

In addition, linagliptin is less likely to be eliminated to a therapeutically meaningful extent through hemodialysis or peritoneal dialysis. Therefore, no dose adjustment of linagliptin is necessary in 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

The mean AUC and C of linagliptin in patients with mild-moderate and severe hepatic impairment (according to the Child-Pugh classification) were similar to those in 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. According to a population pharmacokinetic analysis of phase I and phase II data, body mass index did not have a clinically meaningful effect on the pharmacokinetics of linagliptin.

Sex

It is not necessary to adjust the dose based on gender. According to a population pharmacokinetic analysis of phase I and phase II data, gender had no clinically relevant effect on the pharmacokinetics of linagliptin.

Elderly

No dose adjustment based on age is necessary, because according to a population pharmacokinetic analysis of phase I and phase II data, age did not have a clinically significant impact on the pharmacokinetics of linagliptin. Elderly subjects (65 to 80 years of age) had no different plasma linagliptin concentrations from 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 pharmacokinetic characteristics of linagliptin were found 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.

Metformin

Absorb

Following a single oral dose of metformin, Tmax is reached in 2.5 hours. The absolute bioavailability of metformin hydrochloride 500 mg or 850 mg tablets in healthy volunteers is approximately 50-60%. After an oral dose, the fraction of unabsorbed drugs recovered in the faeces is 20-30%.

Following oral administration, metformin hydrochloride is incompletely absorbed and may saturate. The absorbed phase pharmacokinetics of metformin hydrochloride is expected to be non-linear.

At the dose and dose regimens of metformin hydrochloride, steady-state plasma concentrations are achieved within 24 to 48 hours and are usually less than 1 microgram/mL. In controlled clinical trials, the maximum plasma concentration of metformin hydrochloride (Cmax) did not exceed 5 micrograms/mL even at the maximum dose.

Food reduces the extent and does not significantly slow down the absorption of metformin hydrochloride. Following a dose of 850 mg, a 40% decrease in peak plasma concentrations, a 25% decrease in AUC (area under the curve), and a 35 % increase in time to peak plasma concentration were observed. minute. The clinical significance of this reduction is unknown.

Distribution

The drug is not significantly bound to plasma proteins. Metformin hydrochloride is distributed into erythrocytes. Peak blood concentrations are lower than peak plasma concentrations and occur around the same time. It is highly likely that the erythrocyte is a secondary distribution compartment. The mean volume of distribution (Vd) ranges from 63-276 L.

Metabolism

Metformin hydrochloride is excreted unchanged in the urine. No metabolites were detected in humans.

Elimination

The renal clearance of metformin hydrochloride >400 mL/min indicates that metformin hydrochloride is eliminated by glomerular filtration and tubular secretion. After an oral dose, the apparent half-life is approximately 6.5 hours.

As renal function declines, renal clearance decreases in proportion to creatinine clearance, so the half-life is prolonged, leading to increased plasma concentrations of metformin hydrochloride.

Children

Single-dose study: Following a single dose of metformin 500 mg, the pharmacokinetics in pediatric patients were similar to those in healthy adults.

Multiple-dose study: Limited data with one study. Following repeated dosing of 500 mg twice daily for 7 days in pediatric patients, peak plasma concentrations (Cmax) and systemic exposures (AUC0-t) decreased by 33% and 40 %, respectively. % of adult patients with diabetes receiving repeated doses of 500 mg twice daily for 14 days. Because the dose of the drug is adjusted based on blood glucose levels, this finding is of little clinical significance.

Renal failure

Data in patients with moderate renal impairment are rare and are not reliable enough to warrant an estimate of the systemic exposure to metformin in this group of patients compared with patients with normal renal function. Therefore, when adjusting the dose, clinical efficacy/tolerability should be considered.

Indications and uses

Trajenta Duo is indicated as an adjunct to appropriate diet and exercise to improve glycemic control in adult patients with type 2 diabetes who should be treated concomitantly with linagliptin and metformin. adequate glycemic control with metformin monotherapy or in patients receiving good glycemic control on concomitant treatment with linagliptin and metformin alone.

Trajenta Duo is indicated in combination with a sulphonylurea (i.e., a 3-drug regimen) with appropriate diet and exercise in patients with inadequate glycemic control with a maximal dose of metformin and a sulphonylurea. tolerable.

Dosage and Administration

The recommended dose of Trajenta Duo

The recommended dose is 2.5/500 mg, 2.5/850 mg, or 2.5/1000 mg twice daily.

Dose selection should be based on the current regimen, efficacy, and tolerability of the individual patient. The maximum recommended daily dose of Trajenta Duo is 5 mg linagliptin and 2000 mg metformin.

Trajenta Duo should be taken with a meal, with a gradual increase in dose to reduce the gastrointestinal side effects associated with metformin.

Patients not recently treated with metformin

For patients not recently treated with metformin, the recommended starting dose is 2.5 mg linagliptin/500 mg metformin hydrochloride twice daily.

Patients with inadequate glycemic control with the maximum dose of metformin monotherapy

For patients who have not had good glycemic control with metformin monotherapy, the usual starting dose of Trajenta Duo should provide linagliptin 2.5 mg twice daily (5 mg total daily dose) and metformin at a dose of 2.5 mg twice daily use.

Patient switching from a combination of linagliptin and metformin only

For patients switching from linagliptin and metformin alone to a fixed-dose combination, Trajenta Duo should be started at the patient's current linagliptin and metformin dose.

Patients with inadequate glycemic control on a dual-drug regimen consisting of metformin and a sulphonylurea at the maximum tolerable dose

A dose of Trajenta Duo containing 2.5 mg of linagliptin twice daily (5 mg total daily dose) and a dose of metformin should be used at the same dose as the patient is taking. When Trajenta Duo is combined with a sulphonylurea, a lower dose of sulphonylurea may be required due to the risk of hypoglycemia.

Corresponding to different metformin dosage levels, Trajenta Duo is available in 2.5 mg linagliptin plus 500 mg metformin hydrochloride, 850 mg metformin hydrochloride, or 1000 mg metformin hydrochloride.

The recommended dose of metformin

The starting dose for patients not taking metformin is 500 mg once daily orally. If the patient does not experience gastrointestinal adverse reactions and the dose needs to be increased, an additional 500 mg may be given at intervals of 1 to 2 weeks. Dosage of metformin should be individually adjusted based on efficacy and tolerability and should not exceed the maximum recommended dose of 2000 mg/day.

Recommended use in patients with renal failure

Assess renal function prior to initiation of metformin therapy and periodically thereafter.

Metformin is contraindicated in patients with an eGFR less than 30 mL/min/1.73 m2.

Initiation of metformin therapy is not recommended in patients with an eGFR between 30-45 mL/min/1.73 m2.

In patients taking metformin and whose eGFR falls below 45 mL/min/1.73 m2, assess the risk-benefit of continuing treatment.

Discontinue metformin if the patient's eGFR falls below 30 mL/min/1.73 m2.

Discontinue metformin during iodinated contrast imaging tests

In patients with an eGFR between 30-60 mL/min/1.73m2, in patients with a history of liver disease, alcoholism, or heart failure, or in patients who will receive contrast media Intra-arterial iodide, discontinue metformin before or at the time of imaging with iodinated contrast media. Reassess eGFR after 48 hours, reinstitute metformin if renal function is stable.

Liver failure

Trajenta Duo is contraindicated in patients with hepatic impairment due to the drug-containing metformin.

Elderly

Because metformin is excreted by the kidneys and elderly patients tend to have impaired renal function, renal function should be monitored frequently in elderly patients treated with Trajenta Duo.

Children and adolescents

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

Missed dose

If a dose is missed, it should be taken as soon as the patient remembers it.

However, a double dose should not be taken at the same time. In that case, the missed dose should be skipped.

Warning

General warning

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

Use with drugs known to cause hypoglycemia

Linagliptin

Drugs that stimulate insulin secretion and insulin are known to cause hypoglycemia. In a clinical study, the use of linagliptin in combination with an insulin secretagogue (eg, a sulfonylurea) was associated with a higher incidence of hypoglycaemia than placebo. The incidence of hypoglycaemia is higher when linagliptin is used in combination with insulin in patients with severe renal impairment. Therefore, to reduce the risk of hypoglycemia when used in combination with Trajenta Duo, a lower dose of an insulin secretagogue or insulin may be required.

Metformin

Hypoglycaemia is not present in patients receiving metformin monotherapy under normal circumstances but may occur when calorie intake is inadequate, during strenuous exercise without adequate compensation. calories, or when used concomitantly with other hypoglycemic agents (eg, SU and insulin) or ethanol. Elderly, debilitated, or malnourished patients and those with pituitary or adrenal insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. Hypoglycaemia may be subtle in the elderly, and in patients receiving β-adrenergic blocking agents.

Lactic acidosis

Postmarketing surveillance has documented metformin-associated lactic acidosis, including death, hypothermia, hypotension, and persistent bradyarrhythmias. The onset of metformin-associated lactic acidosis is often subtle, accompanied by atypical symptoms such as malaise, myalgia, respiratory distress, lethargy, and abdominal pain. Metformin-associated lactic acidosis is characterized by increased lactate levels in the blood (>5mmol/L), decreased blood pH, anion gap (no evidence of ketouria or ketoacidosis), increased lactate ratio /pyruvate, and plasma metformin concentrations generally increased >5 µg/mL.

Risk factors for metformin-associated lactic acidosis include renal failure, concomitant use of certain drugs (eg, carbonic anhydrase inhibitors such as topiramate), age 65 years or older, taking Contrast imaging, surgery and other procedures, hypoxia (eg, acute congestive heart failure), heavy alcohol consumption, and liver failure.

Measures to reduce risk and manage metformin-associated lactic acidosis in high-risk patients are detailed in the package insert (Dosage and Administration, Contraindications, Contraindications). Warnings and Precautions, Drug Interactions and Use in Special Populations).

If metformin-associated lactic acidosis is suspected, metformin should be discontinued, the patient promptly referred to the hospital, and management instituted. In patients already treated with metformin, diagnosed with lactic acidosis, or suspected of having a high likelihood of developing lactic acidosis, prompt dialysis is recommended to correct the acidosis and remove accumulated metformin. metformin hydrochloride is dialyzable with a clearance of 170 mL/min under good hemodynamic conditions). Hemodialysis can reverse symptoms and restore recovery.

Educate patients and family members about symptoms of lactic acidosis and, if these symptoms occur, discontinue Trajenta Duo and report these symptoms to a physician.

For each risk factor for metformin-associated lactic acidosis, recommendations to help reduce the risk and manage metformin-associated lactic acidosis are as follows:

Renal impairment: Metformin-associated lactic acidosis during postmarketing drug monitoring occurred mainly in patients with severe renal impairment. The risk of metformin accumulation and metformin-associated lactic acidosis increases with the severity of renal failure because metformin is eliminated primarily by the kidneys. Clinical recommendations based on the patient's renal function include:

Before initiating treatment with metformin, it is necessary to estimate the patient's glomerular filtration rate (eGFR).

Metformin is contraindicated in patients with eGFR less than 30 mL/min/1.73m2.

Initiation of metformin therapy is not recommended in patients with an eGFR between 30-45 mL/min/1.73m2.

Collect data on eGFR at least once a year in all patients taking metformin. In patients, at increased risk of renal failure (eg, the elderly) renal function should be evaluated more frequently.

In patients on metformin and whose eGFR falls below 45 mL/min/1.73m2, assess the risk-benefit of continuing the regimen.

Drug Interactions: Concomitant use of metformin with certain drugs may increase the risk of metformin-associated lactic acidosis: patients with impaired renal function lead to significant hemodynamic changes, affecting body weight. acid-base or increase metformin accumulation. Therefore, consider monitoring the patient more frequently.

Patients 65 years of age and older: The risk of metformin-associated lactic acidosis increases with patient age because elderly patients are more likely to have liver, renal, or heart failure than younger patients. Renal function should be assessed more frequently in elderly patients.

Perform diagnostic tests using contrast: Intravascular administration of contrast in patients on metformin therapy may lead to acute deterioration of renal function and lactic acidosis. Discontinue metformin before or at the time of an iodinated contrast scan in patients with an eGFR between 30-60 mL/min/1.73m2, who have a history of liver failure, alcoholics, heart failure, or patients who will receive intravenous iodinated contrast agents. Reassess eGFR 48 hours after screening and reinstitute metformin if renal function is stable.

Surgery or other procedures: The retention of food and fluids during surgery or other procedures may increase the risk of volume depletion, hypotension, and renal failure. Metformin should be temporarily discontinued when the patient has limited food and fluid intake.

Metformin hydrochloride must be discontinued 48 hours before elective surgery with general, spinal, or epidural anesthesia. The drug can be reintroduced 48 hours after surgery or after the patient is back on oral nutrition and only if renal function is determined to be normal.

Inspiratory Hypoxia: Post-marketing follow-up has documented some metformin-associated lactic acidosis occurring in the setting of acute congestive heart failure (particularly when accompanied by hypoperfusion and hypoxemia). ). Cardiovascular collapse (shock), acute myocardial infarction, sepsis, and other conditions associated with hypoxemia are associated with lactic acidosis and may also cause prerenal azotemia. When these events occur, discontinue metformin.

Alcohol consumption: Alcohol has the potential to affect the effects of metformin on lactate metabolism and may in turn increase the risk of metformin-associated lactic acidosis. Warn patients not to drink alcohol while using metformin.

Hepatic impairment: Patients with hepatic impairment may develop metformin-associated lactic acidosis due to impaired lactate elimination leading to increased blood lactate levels. Therefore, the use of metformin should be avoided in patients who have been diagnosed with liver disease through laboratory or clinical evidence.

Pancreatitis

There have been post-marketing reports of acute pancreatitis, including fatal pancreatitis, in patients receiving linagliptin. Read carefully about possible signs and symptoms of pancreatitis. If pancreatitis is suspected, immediately discontinue Trajenta Duo and initiate appropriate treatment. It is not known whether patients with a history of pancreatitis are at increased risk of pancreatitis while taking Trajenta Duo.

Hypersensitivity reactions

There have been post-marketing reports of serious hypersensitivity reactions in patients receiving linagliptin (a component of Trajenta Duo). Reactions include anaphylaxis, angioedema, and skin shedding. The onset of reactions occurred during the first 3 months after initiation of treatment with linagliptin, with a few reports occurring after the first dose. If a serious hypersensitivity reaction is suspected, discontinue Trajenta Duo, evaluate for other possible events, and institute an alternative antidiabetic treatment.

Angioedema has been reported with other dipeptidyl peptidase-4 (DPP-4) inhibitors. Use with caution in patients with a history of angioedema due to prior use of a DPP-4 inhibitor as it is not known whether these patients may develop angioedema during treatment with Trajenta Duo.

Vitamin B12 concentration

In a 29-week controlled clinical study with metformin, approximately 7% of metformin-treated patients had subnormal and clinically asymptomatic reductions in vitamin B12 levels. This decrease in vitamin B12 levels may be due to interference in vitamin B12 absorption from the B12 intrinsic factor complex, however, is rarely associated with anemia or neurological manifestations due to the short duration (<1 year) in clinical trials. The risk may be more relevant in patients on long-term metformin therapy, and there have been post-marketing adverse reports of hematologic and neurological reactions. Decrease in vitamin B12 levels rapidly reversed when metformin was discontinued or vitamin B12 supplementation was taken. It is recommended that annual hematological parameters be monitored in patients receiving Trajenta Duo and any abnormalities should be reviewed and addressed. In some cases (in patients with deficiency or inadequate absorption of vitamin B12 or calcium) it seems that vitamin B12 levels are easily below normal. In these patients, regular control of serum vitamin B12 levels over a 2-3 year period is beneficial.

Heart function

Patients with heart failure are at higher risk of hypoxia and renal failure. In patients with stable chronic heart failure, Trajenta Duo can be used provided that cardiac and renal function are regularly monitored.

Trajenta Duo is contraindicated in patients with acute and unstable heart failure due to metformin-containing drugs.

Effects on ability to drive and use machines máy

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

Overdose

Symptom

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

Hypoglycaemia did not occur with metformin hydrochloride doses up to 85 g, although lactic acidosis did occur. High doses of metformin hydrochloride or associated risk factors may lead to lactic acidosis. Lactic acidosis is a medical emergency and must be treated in a hospital.

Treatment

In the event of an overdose, the usual supportive treatment measures should be instituted, e.g. removal of unabsorbed drug from the gastrointestinal tract, clinical monitoring, and initiation of necessary therapeutic measures. The most effective means of removing lactate and metformin hydrochloride is dialysis.

Contraindications

Patients with severe renal impairment (eGFR less than 30 mL/min/1.73m2).

The patient has a history of hypersensitivity to metformin/linagliptin or to any of the excipients.

Patients with acute or chronic metabolic acidosis, including diabetic ketoacidosis.

Diabetic pre-coma.

Acute conditions with a risk of affecting renal function such as dehydration, severe infection, shock, use of intravenous iodinated contrast agents.

Diseases that can cause tissue hypoxia (especially acute illness or worsening of chronic conditions) include: decompensated heart failure, respiratory failure, recent myocardial infarction, shock.

Liver failure.

Acute alcohol poisoning.

Alcoholism.

Use in pregnant and lactating women

Pregnancy

No adequate and well-controlled studies have been conducted in pregnant women using Trajenta Duo or its individual active ingredients. Non-clinical reproduction studies conducted in rats using the combination drug Trajenta Duo did not reveal a teratogenic effect of co-administration of linagliptin and metformin.

There are limited data on the use of linagliptin in pregnant women. Nonclinical studies have shown no direct or indirect harmful effects on reproductive toxicity.

There are limited data on the use of metformin in pregnant women. Metformin was not teratogenic in rats at doses of 200 mg/kg/day – four times the human dose. Teratogenic effects were observed in rats with higher doses of metformin (500 and 1000 mg/kg/day – 11 and 23 times the human dose).

As a precaution, it is better to avoid the use of Trajenta Duo during pregnancy.

When the patient is planning a pregnancy and during pregnancy, diabetes should not be treated with Trajenta Duo, but insulin should be used to maintain blood glucose levels as close to normal as possible to reduce the risk of fetal malformations. related to abnormal blood sugar levels.

Breastfeeding

There are no animal studies in lactation using the combination of metformin and linagliptin. Non-clinical studies with individual active ingredients have shown that both metformin and linagliptin are excreted in the milk of lactating rats. In humans, metformin is excreted in human milk. It is not known whether linagliptin is excreted in human milk. Trajenta Duo should not be used by women who are breastfeeding.

Fertility

No studies on the effects of Trajenta Duo on human fertility have been conducted. No adverse effects of linagliptin on fertility were observed in nonclinical studies up to the maximum dose of 240 mg/kg/day (>900 times the human dose).

Pharmacokinetic interactions

General

Co-administration of multiple doses of linagliptin (10 mg once daily) and metformin (850 mg twice daily) in healthy volunteers had no significant effect on the pharmacokinetics of either linagliptin or metformin.

Trajenta Duo pharmacokinetic interaction studies have not been conducted; however, studies of this type have been conducted with the individual active ingredients of Trajenta Duo, linagliptin, and metformin.

Linagliptin

In vitro drug interaction assessment

Linagliptin is a weak to moderate mechanism-based and weakly competitive inhibitor of the CYP isoenzyme 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 cause interactions with other P-gp substrates.

The clinical data presented below suggest that the risk of clinically significant interactions with concomitant drug use is low. No clinically significant interactions requiring dose adjustment were observed.

Linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, pioglitazone, warfarin, digoxin or oral contraceptives, which provides in vivo evidence of a tendency towards fewer drug interactions. with substrates of CYP3A4, CYP2C9, CYP2C8, P-glycoprotein, and organic cationic transporter (OCT).

Metformin: In healthy volunteers, co-administration of metformin 850 mg three times a day 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.

Sulphonylureas: 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.

Thiazolidinediones: Co-administration of multiple daily doses of 10 mg linagliptin (above the therapeutic threshold) with multiple daily doses of 45 mg pioglitazone - a CYP2C8 and CYP3A4 substrate - had no clinical effect on the pharmacokinetics of both linagliptin and pioglitazone or active metabolites of pioglitazone, this indicates that linagliptin is not an inhibitor of CYP2C8-mediated metabolism in vivo and supports the conclusion that inhibition of CYP3A4 in vivo by linagliptin is not warranted. tell.

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 increased linagliptin AUC and Cmax by approximately 2- and 3-fold, respectively. Simulations of steady-state plasma linagliptin concentrations in the presence and absence of ritonavir showed that increases in drug concentrations were not associated with increased accumulation. Changes in the pharmacokinetics of linagliptin are not expected to be clinically significant. Therefore, clinically significant interactions are expected to be unlikely with P-glycoprotein/CYP3A4 inhibitors and no dose adjustment is required.

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 a 39.6% and 43.8% reduction in linagliptin AUC and Cmax, respectively, and an approximately 30% reduction in DPP-4 inhibition at trough concentrations. Therefore, the combination of linagliptin and potent P-gp inducers is expected to be clinically effective, although full efficacy may not be achieved.

Digoxin: Co-administration of multiple daily doses of 5 mg linagliptin with multiple doses of 0.25 mg digoxin in healthy volunteers had no effect on the pharmacokinetics of digoxin. Thus, in vivo, linagliptin is not an inhibitor of P-glycoprotein-mediated transport.

Warfarin: Multiple daily doses of 5 mg linagliptin did not alter the pharmacokinetics of the S(-) or R(+) isomer of warfarin, a CYP2C9 substrate, indicating that linagliptin is not an inhibitor of CYP2C9.

Simvastatin: In healthy volunteers, multiple daily doses of 10 mg linagliptin (above therapeutic range) had minimal effect on the steady-state pharmacokinetics of simvastatin, a sensitive CYP3A4 substrate. After co-administration of 10 mg linagliptin with 40 mg 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 no dose adjustment of CYP3A4-metabolized substrates is necessary when used concomitantly.

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

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

Metformin

The risk of lactic acidosis is increased in patients with acute alcohol intoxication (especially in cases of fasting, malnutrition or liver failure) due to the active ingredient metformin of Trajenta Duo. Alcohol and drugs containing alcohol should be avoided.

Cationic drugs that are eliminated primarily by the tubules (eg, cimetidine) may interact with metformin by competing for systemic tubular transport. A study conducted on 7 healthy volunteers showed that cimetidine 400 mg twice daily increased systemic metformin exposure (AUC) by 50% and Cmax by 81%. Therefore, close blood glucose monitoring, dose adjustment within the recommended dose range, and alteration of diabetes treatment should be considered when co-administered with cationic drugs that are excreted via the renal tubules.

Carbonic anhydrase inhibitors

Topiramate or carbonic anhydrase inhibitors (zonisamide, acetazolamide, or dichlorphenamide) frequently cause a decrease in serum bicarbonate and a hyperchloremic metabolic acidosis, with no change in the anion gap. Concomitant use of these drugs may cause metabolic acidosis. These drugs should be used with caution in patients treated with Trajenta Duo because of the possible increased risk of lactic acidosis.

Intravascular administration of contrast in patients receiving metformin therapy may lead to an acute decline in renal function and lactic acidosis. Discontinue metformin before or at the time of an iodinated contrast scan in patients with an eGFR between 30-60 mL/min/1.73m2, who have a history of liver failure, alcoholics, heart failure, or patients who will receive intravenous iodinated contrast agents. Reassess eGFR 48 hours after screening and reinstitute metformin if renal function is stable.

Side effects

The safety of linagliptin 2.5 mg twice daily (or a bioequivalent dose of 5 mg once daily) in combination with metformin was evaluated in 6,800 patients with type 2 diabetes.

In placebo-controlled studies, more than 1800 patients were treated with 2.5 mg of linagliptin twice daily (or the bioequivalent of 5 mg linagliptin once daily) in combination with metformin for ≥ 12 months. /24 weeks.

In a meta-analysis of placebo-controlled trials, the overall incidence of adverse events in patients receiving placebo and metformin was similar to that in the linagliptin 2.5 mg and metformin groups (54.3% and 49.0%).

The rate of discontinuation due to adverse events in the placebo plus metformin group was similar to that in the linagliptin and metformin combination (3.8% and 2.9%).

Because of the effect of baseline treatment on adverse events (eg, hypoglycemia), adverse events were analyzed and presented based on the respective regimen in addition to metformin treatment. and in addition to metformin in combination with sulphonylurea.

Placebo-controlled studies included 7 studies in which linagliptin was added to metformin treatment and 1 study in which linagliptin was added to metformin+sulphonylurea treatment.

In placebo-controlled studies, the most commonly reported adverse reaction with linagliptin + metformin was diarrhea (1.6%) with a similarly low incidence in the metformin+placebo group (2, 4%).

Adverse reactions reported with the combination of linagliptin and metformin with SU

When linagliptin and metformin were combined with a sulphonylurea, hypoglycemia was the most common adverse event (23.9% in the linagliptin plus metformin plus sulphonylurea group vs 16.0% in the placebo group) and was thought to be a reaction to additional adverse effects. No episodes of hypoglycemia were classified as serious.

Adverse reactions when linagliptin and metformin are combined with insulin

When linagliptin and metformin were used in combination with insulin, the most common adverse event reported was hypoglycemia, but occurred at a similar rate when placebo and metformin were combined with insulin (linagliptin plus metformin) and insulin were 29.5% vs 30.9% in the placebo group with metformin and insulin) with a low rate of serious events (1.5% vs. 0.9%).

Additional information about individual ingredients

Adverse events previously reported with the individual components of the drug may represent a potential adverse effect of Trajenta Duo even if not observed in clinical trials with this preparation.

All adverse events reported in patients receiving linagliptin monotherapy have been reported with Trajenta Duo and include adverse reactions.

Additional adverse reactions reported when linagliptin and metformin were combined with insulin

When linagliptin and metformin were combined with insulin, an additional adverse reaction of constipation was identified.

Preservation

Do not store above 30°C.

Store in original packaging to avoid moisture.

Presentation and packaging

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