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טרג'נטה TRAJENTA (LINAGLIPTIN)

תרופה במרשם תרופה בסל נרקוטיקה ציטוטוקסיקה

צורת מתן:

פומי : PER OS

צורת מינון:

טבליות מצופות פילם : FILM COATED TABLETS

Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

14.2. Pharmacodynamics
Linagliptin binds to DPP-4 in a reversible manner and thus increases the concentrations of incretin hormones. Linagliptin glucose dependently increases insulin secretion and lowers glucagon secretion, thus resulting in better regulation of glucose homeostasis. Linagliptin binds selectively to DPP-4, and selectively inhibits DPP-4 but not DPP-8 or DPP-9 activity in vitro at concentrations approximating therapeutic exposures.

Cardiac Electrophysiology
In a randomized, placebo-controlled, active-comparator, 4-way crossover study, 36 healthy subjects were administered a single oral dose of linagliptin 5 mg, linagliptin 100 mg (20 times the recommended dose), moxifloxacin, and placebo. No increase in QTc was observed with either the recommended dose of 5 mg or the 100-mg dose. At the 100-mg dose, peak linagliptin plasma concentrations were approximately 38- fold higher than the peak concentrations following a 5-mg dose.

Pharmacokinetic Properties

14.3.   Pharmacokinetics

The pharmacokinetics of linagliptin has been characterized in healthy subjects and patients with type 2 diabetes mellitus. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5 hours post dose (Tmax); the mean plasma area under the curve (AUC) was 139 nmol*h/L and maximum concentration (Cmax) was 8.9 nmol/L.

Plasma concentrations of linagliptin decline in at least a biphasic manner with a long terminal half-life (>100 hours), related to the saturable binding of linagliptin to DPP-4. The prolonged elimination phase does not contribute to the accumulation of the drug. The effective half-life for accumulation of linagliptin, as determined from oral administration of multiple doses of linagliptin 5 mg, is approximately 12 hours. After once-daily dosing, steady-state plasma concentrations of linagliptin 5 mg are reached by the third dose, and Cmax and AUC increased by a factor of 1.3 at steady state compared with the first dose.
The intra-subject and inter-subject coefficients of variation for linagliptin AUC were small (12.6% and 28.5%, respectively). Plasma AUC of linagliptin increased in a less than dose-proportional manner in the dose range of 1 to 10 mg. The pharmacokinetics of linagliptin is similar in healthy subjects and in patients with type 2 diabetes mellitus.
Absorption

Trajenta                                                                      Updated Prescribing Information Film coated tablets 5 mg                                                                            July 2024 The absolute bioavailability of linagliptin is approximately 30%. A high-fat meal reduced Cmax by 15% and increased AUC by 4%; this effect is not clinically relevant. TRAJENTA may be administered with or without food.

Distribution
The mean apparent volume of distribution at steady-state following a single intravenous dose of linagliptin 5 mg to healthy subjects is approximately 1,110 L, indicating that linagliptin extensively distributes to the tissues. Plasma protein binding of linagliptin is concentration-dependent, decreasing from about 99% at 1 nmol/L to 75%-89% at ≥30 nmol/L, reflecting saturation of binding to DPP-4 with increasing concentration of linagliptin. At high concentrations, where DPP-4 is fully saturated, 70% to 80% of linagliptin remains bound to plasma proteins and 20% to 30% is unbound in plasma. Plasma binding is not altered in patients with renal or hepatic impairment.

Elimination
Linagliptin has a terminal half-life of about 200 hours at steady-state, though the accumulation half-life is about 11 hours. Renal clearance at steady-state was approximately 70 mL/min.

Metabolism
Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged, indicating that metabolism represents a minor elimination pathway. A small fraction of absorbed linagliptin is metabolized to a pharmacologically inactive metabolite, which shows a steady-state exposure of 13.3% relative to linagliptin.

Excretion
Following administration of an oral [14C]-linagliptin dose to healthy subjects, approximately 85% of the administered radioactivity was eliminated via the enterohepatic system (80%) or urine (5%) within 4 days of dosing.

Specific Populations
Patients with Renal Impairment
An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5 mg in male and female patients with varying degrees of chronic renal impairment. The study included 6 healthy subjects with normal renal function (creatinine clearance [CrCl] ≥80 mL/min), 6 patients with mild renal impairment (CrCl 50 to <80 mL/min), 6 patients with moderate renal impairment (CrCl 30 to <50 mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl <30 mL/min), and 11 patients with type 2 diabetes mellitus and normal renal function. Creatinine clearance was measured by 24-hour urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula.

Under steady-state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects.

In patients with moderate renal impairment under steady-state conditions, mean exposure of linagliptin increased (AUCτ,ss by 71% and Cmax by 46%) compared with healthy subjects. This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function.

Patients with type 2 diabetes mellitus and severe renal impairment showed steady-state exposure approximately 40% higher than that of patients with type 2 diabetes mellitus and normal renal function (increase in AUCτ,ss by 42% and Cmax by 35%). For both type 2 diabetes mellitus groups, renal excretion was below 7% of the administered dose.

These findings were further supported by the results of population pharmacokinetic analyses.

Trajenta                                                                      Updated Prescribing Information Film coated tablets 5 mg                                                                            July 2024 Patients with Hepatic Impairment
In patients with mild hepatic impairment (Child-Pugh class A), steady-state exposure (AUCτ,ss) of linagliptin was approximately 25% lower and Cmax,ss was approximately 36% lower than in healthy subjects. In patients with moderate hepatic impairment (Child-Pugh class B), AUCss of linagliptin was about 14% lower and Cmax,ss was approximately 8% lower than in healthy subjects. Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC0-24 and approximately 23% lower Cmax compared with healthy subjects. Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition.

Effects of Age, Body Mass Index (BMI), Gender and Race

Based on the population pharmacokinetic analysis, age, BMI, gender and race do not have a clinically meaningful effect on the pharmacokinetics of linagliptin [see Use in Specific Populations (11.4)] 
Drug Interaction Studies

In vitro Assessment of Drug Interactions
Linagliptin is a weak to moderate inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes and is not an inducer of CYP isozymes, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11.

Linagliptin is a P-glycoprotein (P-gp) substrate, and inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and in vivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations.

In vivo Assessment of Drug Interactions

Strong inducers of CYP3A4 or P-gp (e.g., rifampin) decrease exposure to linagliptin to subtherapeutic and likely ineffective concentrations [see Drug Interactions (10)]. In vivo studies indicated evidence of a low propensity for causing drug interactions with substrates of CYP3A4, CYP2C9, CYP2C8, P-gp and organic cationic transporter (OCT).
Table 3 describes the effect of coadministered drugs on systemic exposure of linagliptin.

Table 3 Effect of Coadministered Drugs on Systemic Exposure of Linagliptin Geometric Mean Ratio
Coadministered                 Dosing of                  Dosing of              (ratio with/without Drug                  Coadministered Drug*           Linagliptin*           coadministered drug) No effect = 1.0
†
AUC                    Cmax
Metformin             850 mg TID                 10 mg QD                1.20                   1.03 #
Glyburide             1.75 mg                    5 mg QD                 1.02                   1.01 Pioglitazone          45 mg QD                   10 mg QD                1.13                   1.07 Ritonavir             200 mg BID                 5 mg#                   2.01                   2.96 Rifampin**            600 mg QD                  5 mg QD                 0.60                   0.56 *Multiple dose (steady-state) unless otherwise noted
**For information regarding clinical recommendations [see Drug Interactions (10.1)].
#Single dose
†
AUC = AUC(0 to 24 hours) for single-dose treatments and AUC = AUC(TAU) for multiple dose treatments QD = once daily
BID = twice daily
TID = three times daily

Trajenta                                                                       Updated Prescribing Information Film coated tablets 5 mg                                                                             July 2024 Table 4 describes the effect of linagliptin on systemic exposure of coadministered drugs.

Table 4 Effect of Linagliptin on Systemic Exposure of Coadministered Drugs 
Geometric Mean Ratio
Coadministered                 Dosing of                Dosing of      (ratio with/without coadministered Drug                  Coadministered Drug*         Linagliptin*                   drug) No effect = 1.0
AUC†       Cmax
Metformin                  850 mg TID              10 mg QD             metformin        1.01       0.89 #
Glyburide                  1.75 mg                 5 mg QD              glyburide           0.86           0.86 pioglitazone metabolite M-       0.94           0.86
Pioglitazone               45 mg QD                10 mg QD             III                 0.98           0.96 metabolite M-       1.04           1.05
IV
Digoxin                    0.25 mg QD              5 mg QD              digoxin             1.02           0.94 simvastatin         1.34           1.10
Simvastatin                40 mg QD                10 mg QD simvastatin acid    1.33           1.21
R-warfarin          0.99           1.00
S-warfarin          1.03           1.01
Warfarin                   10 mg#                  5 mg QD
INR                 0.93**         1.04**
PT                  1.03**         1.15** ethinylestradiol 0.03
Ethinylestradiol                                                  ethinylestradiol 1.01                    1.08 mg and levonorgestrel     5 mg QD and levonorgestrel                                                levonorgestrel    1.09                   1.13 0.150 mg QD
*Multiple dose (steady-state) unless otherwise noted
#Single dose
†
AUC = AUC(INF) for single dose treatments and AUC = AUC(TAU) for multiple dose treatments **AUC=AUC(0-168) and Cmax=Emax for pharmacodynamic end points
INR = International Normalized Ratio
PT = Prothrombin Time
QD = once daily
TID = three times daily

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